Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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Effects of stress and cortisol on the polarization of carp macrophages
Maciuszek, Magdalena ; Rydz, Leszek ; Świtakowska, Iga ; Verburg-van Kemenade, Lidy ; Chadzińska, Magdalena - \ 2019
Fish and Shellfish Immunology 94 (2019). - ISSN 1050-4648 - p. 27 - 37.
Carp - Cortisol - Head kidney - Monocytes/macrophages - Stress - Trunk kidney

In teleost fish, myelopoiesis is maintained both in the head (HK) and trunk kidney (TK), but only the HK holds the endocrine cells that produce the stress hormone cortisol. We now compared the effects of prolonged restraint stress (in vivo) and cortisol (in vitro) on the polarization of HK and TK-derived carp macrophages. Monocytes/macrophages from both sources were treated in vitro with cortisol, lipopolysaccharide or with both factors combined. In vivo, fish were challenged by a prolonged restraint stress. Gene expression of several markers typical for classical M1 and alternative M2 macrophage polarization, as well as glucocorticoid receptors, were measured. Cells from both sources did not differ in the constitutive gene expression of glucocorticoid receptors, whereas they significantly differed in their response to cortisol and stress. In the LPS-stimulated HK monocytes/macrophages, cortisol in vitro counteracted the action of LPS while the effects of cortisol on the activity of TK monocytes/macrophages were less explicit. In vivo, restraint stress up-regulated gene expression of M2 markers in freshly isolated HK monocytes/macrophages, while at the same time it did not affect TK monocytes/macrophages. Moreover, LPS-stimulated HK monocytes/macrophages from stressed animals showed only minor differences in the gene expression of M1 and M2 markers, compared to LPS-treated monocytes/macrophages from control fish. In contrast, stress-induced changes in TK-derived LPS-treated cells were more pronounced. However, these changes did not clearly indicate whether in TK monocytes/macrophages stress will stimulate classical or alternative polarization. Altogether, our results imply that cortisol in vitro and stress in vivo direct HK, but not TK, monocytes/macrophages to the path of alternative polarization. These findings reveal that like in mammals, also in fish the glucocorticoids form important stimulators of alternative macrophage polarization.

A role for CXC chemokines and their receptors in stress axis regulation of common carp
Pijanowski, Lukasz ; Verburg-van Kemenade, Lidy ; Chadzinska, Magdalena - \ 2019
General and Comparative Endocrinology 280 (2019). - ISSN 0016-6480 - p. 194 - 199.
Carp - CXC chemokines - CXC receptors - Stress

Although chemokines mainly function to activate leukocytes and to direct their migration, novel evidence indicates non-immune functions for chemokines within the nervous and endocrine systems. These include development of the nervous system, neuromodulation, neuroendocrine regulation and direct neurotransmitter-like actions. In order to clarify a potential role for chemokines and their receptors in the stress response of fish, we studied changes in the expression patterns of CXC ligands and their receptors in the stress axis organs of carp, during a restraint stress procedure. We showed that stress down-regulated the gene expression of CXCL9-11 (CXCb1 and CXCb2)in stress axis organs and up-regulated expression of CXCR4 chemokine receptor in NPO and pituitary. Moreover, upon stress, reduced gene expression of CXCL12a and CXCL14 was observed in the head kidney. Our results imply that in teleost fish, CXC chemokines and their receptors are involved in neuroendocrine regulation. The active regulation of their expression in stress axis organs during periods of restraint indicates a significant role in the stress response.

Stress differentially affects the systemic and leukocyte estrogen network in common carp
Szwejser, Ewa ; Pijanowski, Lukasz ; Maciuszek, Magdalena ; Ptak, Anna ; Wartalski, Kamil ; Duda, Malgorzata ; Segner, Helmut ; Kemenade, Lidy van; Chadzinska, Magdalena - \ 2017
Fish and Shellfish Immunology 68 (2017). - ISSN 1050-4648 - p. 190 - 201.
17β-estradiol - Aromatase - Carp - Estrogen receptors - Leukocytes - Stress

Both systemic and locally released steroid hormones, such as cortisol and estrogens, show immunomodulatory actions. This research gives evidence that circulating and leukocyte-derived estrogens can be involved in the regulation of the immune response in common carp, during homeostasis and upon restraining stress. It was found that stress reduced level of blood 17β-estradiol (E2) and down-regulated the gene expression of components of the “classical” estrogen system: the nuclear estrogen receptors and the aromatase CYP19, in the hypothalamus, the pituitary and in the ovaries. In contrast, higher gene expression of the nuclear estrogen receptors and cyp19a was found in the head kidney of stressed animals. Moreover, stress induced changes in the E2 level and in the estrogen sensitivity at local/leukocyte level. For the first time in fish, we showed the presence of physiologically relevant amounts of E2 and the substrates for its conversion (estrone – E1 and testosterone – T) in head kidney monocytes/macrophages and found that its production is modulated upon stress. Moreover, stress reduced the sensitivity of leukocytes towards estrogens, by down-regulation the expression of the erb and cyp19 genes in carp phagocytes. In contrast, era expression was up-regulated in the head kidney monocytes/macrophages and in PBLs derived from stressed animals. We hypothesize that, the increased expression of ERα, that was observed during stress, can be important for the regulation of leukocyte differentiation, maturation and migration. In conclusion, these results indicate that, in fish, the estrogen network can be actively involved in the regulation of the systemic and local stress response and the immune response.

Estrogen-dependent seasonal adaptations in the immune response of fish
Szwejser, Ewa ; Kemenade, Lidy van; Maciuszek, Magdalena ; Chadzinska, Magdalena - \ 2017
Hormones and Behavior 88 (2017). - ISSN 0018-506X - p. 15 - 24.
Aromatase - Endocrine disrupting compounds - Estrogen receptors - Estrogens - Fish - Season

Clinical and experimental evidence shows that estrogens affect immunity in mammals. Less is known about this interaction in the evolutionary older, non-mammalian, vertebrates. Fish form an excellent model to identify evolutionary conserved neuroendocrine-immune interactions: i) they are the earliest vertebrates with fully developed innate and adaptive immunity, ii) immune and endocrine parameters vary with season, and iii) physiology is constantly disrupted by increasing contamination of the aquatic environment.Neuro-immuno-endocrine interactions enable adaption to changing internal and external environment and are based on shared signaling molecules and receptors. The presence of specific estrogen receptors on/in fish leukocytes, implies direct estrogen-mediated immunoregulation. Fish leukocytes most probably are also capable to produce estrogens as they express the . cyp19a and . cyp19b - genes, encoding aromatase cytochrome P450, the enzyme critical for conversion of C19 steroids to estrogens.Immunoregulatory actions of estrogens, vary among animal species, and also with dose, target cell type, or physiological condition (e.g., infected/non-infected, reproductive status). They moreover are multifaceted. Interestingly, season-dependent changes in immune status correlate with changes in the levels of circulating sex hormones. Whereas E2 circulating in the bloodstream is perhaps the most likely candidate to be the physiological mediator of systemic immune-reproductive trade-offs, leukocyte-derived hormones are hypothesized to be mainly involved in local tuning of the immune response. Contamination of the aquatic environment with estrogenic EDCs may violate the delicate and precise allostatic interactions between the endogenous estrogen system and the immune system. This has negative effects on fish health, but will also affect the physiology of its consumers.

The immunomodulatory role of the hypothalamus-pituitary-gonad axis : Proximate mechanism for reproduction-immune trade offs?
Segner, Helmut ; Kemenade, Lidy van; Chadzinska, Magdalena - \ 2017
Developmental and Comparative Immunology 66 (2017). - ISSN 0145-305X - p. 43 - 60.
Evolution - Hypothalamus-pituitary-gonad axis - Immunity - Life history - Neuroendocrine - Reproduction - Trade-off - Vertebrate

The present review discusses the communication between the hypothalamic-pituitary-gonad (HPG) axis and the immune system of vertebrates, attempting to situate the HPG-immune interaction into the context of life history trade-offs between reproductive and immune functions. More specifically, (i) we review molecular and cellular interactions between hormones of the HPG axis, and, as far as known, the involved mechanisms on immune functions, (ii) we evaluate whether the HPG-immune crosstalk serves as proximate mechanism mediating reproductive-immune trade-offs, and (iii) we ask whether the nature of the HPG-immune interaction is conserved throughout vertebrate evolution, despite the changes in immune functions, reproductive modes, and life histories. In all vertebrate classes studied so far, HPG hormones have immunomodulatory functions, and indications exist that they contribute to reproduction-immunity resource trade-offs, although the very limited information available for most non-mammalian vertebrates makes it difficult to judge how comparable or different the interactions are. There is good evidence that the HPG-immune crosstalk is part of the proximate mechanisms underlying the reproductive-immune trade-offs of vertebrates, but it is only one factor in a complex network of factors and processes. The fact that the HPG-immune interaction is flexible and can adapt to the functional and physiological requirements of specific life histories. Moreover, the assumption of a relatively fixed pattern of HPG influence on immune functions, with, for example, androgens always leading to immunosuppression and estrogens always being immunoprotective, is probably oversimplified, but the HPG-immune interaction can vary depending on the physiological and envoironmental context. Finally, the HPG-immune interaction is not only driven by resource trade-offs, but additional factors such as, for instance, the evolution of viviparity shape this neuroendocrine-immune relationship.

Neuroendocrine-immune interaction : Evolutionarily conserved mechanisms that maintain allostasis in an ever-changing environment
Kemenade, Lidy van; Cohen, Nicholas ; Chadzinska, Magdalena - \ 2017
Developmental and Comparative Immunology 66 (2017). - ISSN 0145-305X - p. 2 - 23.
Blood brain barrier - Homeostasis - Leukocytes - Neuroendocrine-immune interaction - Psychoneuroimmunology - Receptor interaction - Stress axis

It has now become accepted that the immune system and neuroendocrine system form an integrated part of our physiology. Immunological defense mechanisms act in concert with physiological processes like growth and reproduction, energy intake and metabolism, as well as neuronal development. Not only are psychological and environmental stressors communicated to the immune system, but also, vice versa, the immune response and adaptation to a current pathogen challenge are communicated to the entire body, including the brain, to evoke adaptive responses (e.g., fever, sickness behavior) that ensure allocation of energy to fight the pathogen. This phenomenon is evolutionarily conserved. Hence it is both interesting and important to consider the evolutionary history of this bi-directional neuroendocrine-immune communication to reveal phylogenetically ancient or relatively recently acquired mechanisms. Indeed, such considerations have already disclosed an extensive "common vocabulary" of information pathways as well as molecules and their receptors used by both the neuroendocrine and immune systems. This review focuses on the principal mechanisms of bi-directional communication and the evidence for evolutionary conservation of the important physiological pathways involved.

A role for multiple estrogen receptors in immune regulation of common carp
Szwejser, Ewa ; Maciuszek, Magdalena ; Casanova-Nakayama, Ayako ; Segner, Helmut ; Kemenade, Lidy van; Chadzinska, Magdalena - \ 2017
Developmental and Comparative Immunology 66 (2017). - ISSN 0145-305X - p. 61 - 72.
17β-estradiol - Carp - Estrogen receptors - GPR30 - Immune response - Monocyte/macrophage

Estrogens are important for bi-directional neuroendocrine-immune interaction. They act via nuclear estrogen receptors (ERα and ERβ) and/or G-protein coupled receptor - GPR30.We found expression of ERα, ERβ and GPR30 in carp lymphoid tissues and head kidney monocytes/macrophages, neutrophils and lymphocytes. Interestingly, ERβ is also expressed in some head kidney lymphocytes but not in naive PBLs. Immune stimulation altered the cell type specific profile of expression of these receptors, which depends on both activation and maturation stage.This implies direct leukocyte responsiveness to estrogen stimulation and therefore in vitro effects of 17β-estradiol (E2) on reactive oxygen species (ROS) production in monocytes/macrophages were determined. Short-time incubation with E2 increased ROS production in PMA-stimulated cells. Results comply with mediation by GPR30, partially functioning via phosphoinositide 3-kinase activation.These results furthermore demonstrate that neuroendocrine-immune communication via estrogen receptors is evolutionary conserved.

The role of estrogen receptors and aromatase in carp leukocyte activation
Szwejser, Ewa ; Maciuszek, Magdalena ; Ptak, Anna ; Segner, H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, Magdalena - \ 2016
Stress-induced adaptation of neutrophilic granulocyte activity in K and R3 carp lines
Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Irnazarow, I. ; Chadzinska, M. - \ 2015
Fish and Shellfish Immunology 47 (2015)2. - ISSN 1050-4648 - p. 886 - 892.
Common carp - IL-10 - NET formation - Neutrophilic granulocytes - Respiratory burst - Stress

Both in mammals and fish, stress induces remarkable changes in the immune response. We focused on stress-induced changes in the activity of neutrophilic granulocytes in the R3 and K lines of common carp, which showed differential stress responses. Our study clearly demonstrates that a prolonged restraint stress differentially affects the activity of K and R3 carp neutrophils. In the K line, stress decreased the respiratory burst, while in the R3 line it reduced the release of extracellular DNA. Surprisingly, the stress-induced changes in ROS production and NET formation did not correlate with changes in gene expression of the inflammatory mediators and GR receptors. In neutrophilic granulocytes from K carp, gene expression of the stress-sensitive cortisol GR1 receptor was significantly higher than in neutrophils from R3 fish, which will make these cells more sensitive to high levels of cortisol. Moreover, upon stress, neutrophilic granulocytes of K carp up-regulated gene expression of the anti-inflammatory cytokine IL-10 while this was not observed in neutrophilic granulocytes of R3 carp.Therefore, we can hypothesize that, in contrast to R3 neutrophils, the more cortisol sensitive neutrophils from K carp respond to stress with up-regulation of IL-10 and consequently reduction of ROS production. Most probably the ROS-independent NET formation in K carp is not regulated by this anti-inflammatory cytokine. These data may indicate a predominantly ROS-independent formation of NETs by carp neutrophilic granulocytes. Moreover, they underline the important role of IL-10 in stress-induced immunoregulation.

Mechanisms involved in the formation of extracellular traps in granuloctyes and macrophages of common carp
Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
GPR30 mediates estradiol-stimulated increase of respiratory burst in carp macrophages
Szwejser, E. ; Casanova-Nakayama, Ayako ; Maciuszek, Magdalena ; Segner, H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Melationin regulates migratory activity and apoptosis of carp phagocytes during inflammation
Kepka, M. ; Szwejser, E. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Immune and neuroendocrine regulation of inflammation in teleost fish
Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Melatonin regulates chemotaxis of carp phagocytes
Kepka, M. ; Szwejser, E. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Expression of nuclear and membrane estrogen receptors in/on lymphoid organs and leukocytes in common carp: indications for neuroendocrine-immune interaction via estrogens
Szwejser, E. ; Casanova-Nakayama, Ayako ; Kepka, M. ; Maciuszek, Magdalena ; Verburg-van Kemenade, B.M.L. ; Segner, H. ; Chadzinska, M.K. - \ 2015
A role for melatonin in maintaining the pro- and anti-inflammatory balance by influencing leukocyte migration and apoptosis in carp
Kepka, M. ; Szwejser, E. ; Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Developmental and Comparative Immunology 53 (2015). - ISSN 0145-305X - p. 179 - 190.
coupled receptor dimerization - messenger-rna expression - pineal hormone melatonin - innate immune parameters - common carp - dna-damage - in-vitro - neutrophilic granulocytes - glucocorticoid-receptor - phagocytic-activity
Melatonin is responsible for the synchronization of many physiological processes, including the immune response. Here we focus on the expression of melatonin MT1 receptors in/on leukocytes, and on the effects of melatonin administration on the inflammatory processes of carp. For the first time, we showed that fish leukocytes express MT1 receptors, implicating direct responsiveness to melatonin stimulation. Moreover, both in vitro and in vivo, melatonin modulated the immune response. The most potent effects of melatonin concerned the regulation of leukocyte migration. Melatonin reduced chemotaxis of leukocytes towards CXC chemokines in vitro. In vivo, during zymosan induced peritonitis, i.p. administration of melatonin reduced the number of neutrophils. This correlated with a melatonin-induced decrease of gene expression of the CXCa chemokine. Moreover, melatonin induced a decrease of the respiratory burst in inflammatory leukocytes. Although these data do suggest a potent anti-inflammatory function for this hormone, melatonin-induced inhibition of leukocyte apoptosis clearly indicates towards a dual function. These results show that also in carp, melatonin performs a pleiotropic and extra-pineal function that is important in maintaining the delicate pro- and anti-inflammatory balance during infection. They furthermore demonstrate that neuroendocrine–immune interaction via melatonin is evolutionary conserved.
Activity of the hypothalamus-pituitary-interrenal axis (HPI axis) and immune response in carp lines with different susceptibility to disease
Pijanowski, L. ; Jurecka, P.M. ; Irnazarow, I. ; Kepka, M. ; Szwejser, E. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Fish Physiology and Biochemistry 41 (2015)5. - ISSN 0920-1742 - p. 1261 - 1278.
The stress response transmitted by the HPA axis is one of the best examples of neuroendocrine–immune interactions that are critical for survival. Analogous to the situation in mammals, the stress response in fish is characterized by the activation of the hypothalamo–pituitary–interrenal axis (HPI). Effects of cortisol on the fish immune system comply with findings in mammals and suggest that the differences in sensitivity to stress will influence the immune response and as a consequence of survival. Therefore, we studied the stress response and its immunity-related effects in four different carp lines (R3, R3xR8, K and R2) that display a differential pathogen susceptibility. Previous studies indicate that R3xR8 and R3 carp are susceptible to bacterial and parasite infection, while R2 and K are relatively resistant to infection. Interestingly, the most striking effect of stress on leukocyte composition and activity was observed in the pathogen-resistant K carp, even though no robust changes in gene expression of stress-involved factors were observed. In contrast, R3 carp showed no spectacular stress-induced changes in their immunological parameters with concurrent significant activation of the HPI axis. Upon stress, the R3 carp showed up-regulation of crf, pomc and gr2 gene expression in the hypothalamus. Furthermore in R3 carp, at all levels of the HPI axis, stress induced the highest up-regulation of il-1ß gene expression. Although we are aware of the complexity of the interactions between stress and pathogen susceptibility and of the risk of interpretation based on correlations, it is noteworthy that the fish more susceptible to infection also exhibited the highest response to stress.
Production of inflammatory mediators and extracellular traps by carp macrophages and neutrophils in response to lipopolysaccharide and/or interferon-¿2
Pijanowski, L. ; Scheer, M.H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2015
Fish and Shellfish Immunology 42 (2015)2. - ISSN 1050-4648 - p. 473 - 482.
toll-like receptors - cyprinus-carpio - signaling pathways - expression analysis - escherichia-coli - immune-response - lps recognition - gene-expression - fish - l.
Neutrophilic granulocytes and macrophages are crucial for the innate immune response against infections. They migrate into the focus of inflammation, where they efficiently bind, engulf and kill bacteria by proteolytic enzymes, antimicrobial peptides, reactive oxygen (ROS) and nitrogen (RNS) species. Moreover, activated neutrophils and macrophages can form extracellular traps (ETs). Fish neutrophils and macrophages are morphologically, histochemically, and functionally similar to their mammalian counterparts, but their significance for regulation of inflammatory responses and pathogen killing needs further elucidation. We compared the activity of head kidney monocytes/macrophages and neutrophilic granulocytes of common carp and established that upon lipopolysaccharide stimulation, not only neutrophils, but also carp monocytes/macrophages release extracellular DNA and are capable to form macrophage extracellular traps (METs). To clarify whether many specific LPS functions reported for piscine phagocytes might be due to impurities in the commonly used LPS preparations we studied expression of inflammatory mediators, release of DNA, ROS and RNS in cells stimulated with LPS or its highly purified form (pLPS). Also IFN-¿2 stimulation and its synergism with LPS/pLPS in stimulating expression of pro-inflammatory mediators was studied. Results substantiate that a classical stimulation of TLR4 by LPS may indeed be absent in carp as most of the classically reported LPS effects are abolished or diminished when pLPS is used. Interestingly, we also observed a potent IL-10 expression in neutrophilic granulocytes upon LPS stimulation, which, apart from their pro-inflammatory function, clearly indicates a role in restrictive control of the inflammatory reaction.
Melatonin affects migration and apoptosis of carp inflammatory leukocytes
Kepka, M. ; Pijanowski, L. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2014
In: 27th conference of european comparative endocrinologists (CECE) 2014 abstracts & programme. - - p. 96 - 96.
Stress response and activity of the hypothalamus-pituitary-interrenal axis (HPI axis) in carp lines with different susceptibility to disease
Pijanowski, L. ; Jurecka, P.M. ; Irnazarow, I. ; Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2014
In: Proceedings of the 27th conference of european comparative endocrinologists (CECE) 2014 abstracts & programme. - - p. 107 - 107.
The stress response is one of the best examples of neuroendocrine-immune interactions. Analogue to the HPA axis in mammals, the stress response in fish is characterized by activation the hypothalamo-pituitary-interrenal (HPI) axis, activation of which starts in the hypothalamic nucleus preopticus (NPO) releasing corticotropic releasing hormone (CRH). CRH stimulates the pituitary to release adrenocorticotropic hormone (ACTH) which is cleaved from pro-opiomelanocortin (POMC). ACTH stimulates release of cortisol from the head kidney. Interestingly, also the crucial pro-inflammatory cytokine IL-1b is involved in both immune and endocrine signalling during stress. Like in mammals, fish leukocytes express receptors for cortisol (GR) and effects of cortisol on the fish immune system generally comply with findings in mammals. This implies that a differential sensitivity to stress may influence the immune response and as a consequence survival. Therefore we studied the stress response in different carp lines that display a differential pathogen susceptibility (R3xR8 and R3 carp are susceptible to bacterial and parasite infection, while R2 and K are relatively resistant). After a stress paradigm of prolonged restraining glucose and cortisol levels were determined, as well as expression of genes involved in HPI axis activity. Stress induced significant increase of serum cortisol levels in all fish lines studied. Both basal and stress-stimulated cortisol levels were higher in the R3xR8 line than in R2, K and R3 fish. In R3 fish we observed stress-induced up-regulation of POMC and GR2 gene expression in the NPO, while in K fish restraining stress slightly down-regulated expression of POMC and GR genes both in NPO and pituitary. Furthermore, both in NPO and pituitary of R3 fish the highest up-regulation of IL- 1b gene expression was observed. Although we are aware of the complexity of the network of connections between stress and susceptibility to pathogens it is striking that the fish more susceptible to infection also exhibit a higher expression of stress related genes.
Mechanisms involved in apoptosis of carp leukocytes upon in vitro and in vivo immunostimulation
Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Homa, J. ; Chadzinska, M.K. - \ 2014
Fish and Shellfish Immunology 39 (2014)2. - ISSN 1050-4648 - p. 386 - 395.
cytochrome-c release - molecular-cloning - cyprinus-carpio - nitric-oxide - transgenic zebrafish - signal-transduction - ceramide generation - respiratory burst - human neutrophils - oxidative stress
During inflammation leukocyte activity must be carefully regulated, as high concentrations and/or prolonged action of pro-inflammatory mediators e.g. reactive oxygen species (ROS) can be detrimental not only for pathogens but also for host tissues. Programmed cell death – apoptosis is a most effective regulatory mechanism for down regulation of leukocyte activity, but little is known about this process in fish. We aimed to reveal the mechanisms of initiation and regulation of apoptosis in carp neutrophilic granulocytes and macrophages. During zymosan-induced peritonitis in carp, activated inflammatory neutrophilic granulocytes and monocytes/macrophages died by apoptosis. This correlated with a strong production of ROS, but pretreatment of the fish with NADPH oxidase inhibitor only slightly decreased late apoptosis. Interestingly in vitro incubation with zymosan or phorbol ester, but not lipopolisaccharide and poli I:C induced apoptosis of head kidney neutrophilic granulocytes. This coincided with loss of mitochondrial membrane potential. Moreover, in zymosan-stimulated neutrophilic granulocytes NADPH oxidase inhibitor not only reduced the production of ROS but also apoptosis. A similar effect was not observed in cells stimulated with phorbol ester, where DPI reduced ROS production, but not apoptosis. In PMA-stimulated neutrophilic granulocytes both the respiratory burst and apoptosis were reduced by protein kinase inhibitor. Furthermore, a short neutrophil stimulation either with PMA or with zymosan did induce caspase-independent apoptosis. These results show that in carp, apoptosis is an important regulatory process during in vitro and in vivo immunostimulation. In neutrophils, protein kinase, but not NADPH oxidase, is involved in PMA-induced apoptosis while apoptosis induced by zymosan is ROS-dependent.
Characterization and expression analysis of an interferon-y2 induced chemokine receptor CXCR3 in common carp (Cyprinus carpio L.)
Chadzinska, M.K. ; Golbach, L.A. ; Pijanowski, L. ; Scheer, M.H. ; Verburg-van Kemenade, B.M.L. - \ 2014
Developmental and Comparative Immunology 47 (2014)1. - ISSN 0145-305X - p. 68 - 76.
central-nervous-system - rheumatoid-arthritis - t-cells - monoclonal-antibodies - molecular evolution - endothelial-cells - phagocytic-cells - teleost fish - b-cells - inflammation
Chemokine and chemokine receptor signalling pairs play a crucial role in regulation of cell migration, morphogenesis, and cell activation. Expressed in mammals on activated T and NK cells, chemokine receptor CXCR3 binds interferon-¿ inducible chemokines CXCL9–11 and CCL21. Here we sequenced the carp CXCR3 chemokine receptor and showed its relationship to CXCR3a receptors found in other teleosts. We found high expression of the CXCR3 gene in most of the organs and tissues of the immune system and in immune-related tissues such as gills and gut, corroborating a predominantly immune-related function. The very high expression in gill and gut moreover indicates a role for CXCR3 in cell recruitment during infection. High in vivo expression of CXCR3 at later stages of inflammation, as well as its in vitro sensitivity to IFN-¿2 stimulation indicate that in carp, CXCR3 is involved in macrophage-mediated responses. Moreover, as expression of the CXCR3 and CXCb genes coincides in the focus of inflammation and as both the CXCb chemokines and the CXCR3 receptor are significantly up-regulated upon IFN-¿ stimulation it is hypothesized that CXCb chemokines may be putative ligands for CXCR3.
In vitro and in vivo immuno stimulation affects apoptosis of carp leukocytes
Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Homa, J. ; Chadzinska, M.K. - \ 2013
Fish and Shellfish Immunology 34 (2013)6. - ISSN 1050-4648 - p. 1658 - 1658.
Apoptosis, programmed cell death, plays a crucial role in many homeostatic processes like tissue development and the elimination of old/unfunctional cells, thereby avoiding the initiation of harmful inflammatory processes. Also during inflammation it is essential to eradicate neutrophils and macrophages that have accomplished their task. In mammals, two main pathways of cell apoptosis have been described, the external (extrinsic) and the internal (intrinsic) – mitochondrial, pathway. The extrinsic pathway is initiated by activation of membrane death receptors that belong to the TNF superfamily and activate initiator caspase-8. The intrinsic route, initiated by e.g. reactive oxygen species (ROS), induces changes in the mitochondrial membrane and activates initiator caspase-9. Both caspase-8 and 9 stimulate effector caspases 3 which play a central role in the execution-phase of cell apoptosis – DNA fragmentation. Moreover, NADPH oxidase-derived ROS induce caspase-independent apoptosis by direct activation of protein kinase transduction pathways ERK1/2, p38 MAPK and JNK. The aim of the present work was to study mechanisms involved in apoptosis of carp neutrophils in vitro upon cell immunostimulation and in vivo – during zymosan-induced peritonitis. Moreover, preliminary results showed that also in vivo during zymosan-induced peritonitis, neutrophils recruited to the focus of inflammation undergo apoptosis of which the peak activity correlates with their maximal respiratory burst activity. It is therefore hypothesized that apoptosis of inflammatory leukocytes – a crucial mechanism for eradication of cells during the resolution phase of inflammation, is at least partly ROS-dependent. In vitro head kidney neutrophils were stimulated either with phorbol ester (PMA) or lipopolysaccharide (LPS). ROS and nitric oxide (NO) production, as well as apoptosis and necrosis were measured. As expected, incubation of cells with PMA induced a robust production of ROS and apoptosis. Both processes were inhibited in cells that were pre-treated with NADPH-oxidase inhibitor DPI and protein kinases (PK) inhibitor – staurosporine but not by treatment with the pan-caspase inhibitor Z-VAD-fmk. These results indicate that PMA-stimulated apoptosis of neutrophils is a ROS and PK but not caspase-dependent phenomenon. Additionally, the role of NO in apoptosis of carp neutrophils was verified upon in vitro cell stimulation with LPS, NO donor – SNAP and iNOS inhibitor – L-NAME. None of these substances did significantly affect the apoptosis of neutrophils.
ROS involvement in the formation of neutrophil extracellular traps in common carp
Pijanowski, L. ; Golbach, L.A. ; Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2013
Fish and Shellfish Immunology 34 (2013)6. - ISSN 1050-4648 - p. 1729 - 1729.
Carp neutrophilic granulocyes form extracellular traps via ROS-dependent and independent pathways
Pijanowski, L. ; Golbach, L.A. ; Kolaczkowska, E. ; Scheer, M.H. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2013
Fish and Shellfish Immunology 34 (2013)5. - ISSN 1050-4648 - p. 1244 - 1252.
differential expression - net formation - teleost fish - myeloperoxidase - bacterial - immunity - genes - l. - matrix-metalloproteinase-9 - streptococcus
Neutrophil extracellular traps (NETs) have recently been described as an important innate defense mechanism that leads to immobilization and killing of invading pathogens. NETs have been identified in several species, but the mechanisms involved in NET formation and their role in infection have not been well determined yet. Here we show that upon in vitro stimulation with different immunostimulants of bacterial, fungal or viral origin, carp neutrophilic granulocytes rapidly release NET structures. We analyzed the composition of these structures and the kinetics of their formation by confocal microscopy, by quantifying the levels of extracellular DNA and the release of enzymes originating from neutrophilic granules: myeloperoxidase, neutrophil elastase and matrix metalloproteinase 9 (MMP-9). Profiles of NET release by carp neutrophils as well as their enzyme composition are stimulus- and time-dependent. This study moreover provides evidence for a stimulus-dependent selective requirement of reactive oxygen species in the process of NET formation. Collectively the results support an evolutionary conserved and strictly regulated mechanism of NET formation in teleost fish.
Neuroendocrine-immune interaction: regulation of inflammation via G-protein coupled receptors
Verburg-van Kemenade, B.M.L. ; Aa, L.M. van der; Chadzinska, M.K. - \ 2013
General and Comparative Endocrinology 188 (2013). - ISSN 0016-6480 - p. 94 - 101.
cyprinus-carpio l. - toll-like receptors - common carp - chemokine receptor - cxc chemokine - expression analysis - innate immunity - teleost fish - gene family - in-vivo
Neuroendocrine- and immune systems interact in a bi-directional fashion to communicate the status of pathogen recognition to the brain and the immune response is influenced by physiological changes. The network of ligands and their receptors involved includes cytokines and chemokines, corticosteroids, classical pituitary hormones, catecholamines and neuropeptides (e.g. opioids), as well as neural pathways. We studied the role of opioid, adrenergic and melatonin G-protein coupled receptors (GPCR) on carp (Cyprinus carpio) leucocytes. Ligand interaction by morphine and adrenaline both in vitro and in vivo resulted in considerable decrease of chemotaxis and expression of CXC chemokines and chemokine CXC receptors. These effects may have substantial influence on the process of inflammation, the efficacy of which is crucial for an effective immune response. Both opioid receptors and chemokine receptors are G-protein coupled receptors (GPCRs), and were classically assumed to function as monomers. This paradigm is now challenged by the emerging concept of homo- and hetero dimerization which may represent the native form of many receptors. G-protein coupling, downstream signaling and regulatory processes such as receptor internalization are largely influenced by the dimeric nature. The true functional importance of GPCR interactions remains enigmatic, but it certainly has implications with respect to the specificity of currently used medications. This review focuses on the important function of chemokine GPCRs during inflammation and the potential neuroendocrine modulation of this process through “neuroendocrine” GPCRs.
Neuroendocrine modulation of the inflammatory response in common carp: adrenaline regulates leukocyte profile and activity
Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2013
General and Comparative Endocrinology 188 (2013). - ISSN 0016-6480 - p. 102 - 109.
beta-adrenergic-receptors - necrosis-factor-alpha - cyprinus-carpio - in-vitro - immune-response - rainbow-trout - neutrophilic granulocytes - interleukin-10 production - opioid receptor - nervous-system
Inflammatory responses have to be carefully controlled, as high concentrations and/or prolonged action of inflammation-related molecules (e.g. reactive oxygen species, nitric oxide and pro-inflammatory cytokines) can be detrimental to host tissue and organs. One of the potential regulators of the inflammatory process are stress mediators including adrenaline. In vivo effects of adrenaline were studied during zymosan-induced (Z) peritoneal inflammation in the common carp Cyprinus carpio L. Adrenaline injected together with zymosan (ZA) did not change the number of inflammatory leukocytes in the peritoneal cavity, however at 24 h post-injection it significantly reduced the percentage of monocytes/macrophages. Moreover, compared to cells retrieved from fish treated with PBS or zymosan only, adrenaline increased the percentage of apoptotic leukocytes in the focus of inflammation. Furthermore, adrenaline significantly reduced the expression of chemokine CXCL8_L1 (a functional homolog of mammalian IL-8) and its receptors (CXCR1 and CXCR2), indicating changes in leukocyte recruitment after stress. We conclude that adrenaline may contribute to a coordinated reaction by influencing the inflammatory response via direct regulation of leukocyte migration and/or apoptosis.
Neuroendocrine receptors regulate immune responses
Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2012
In: 26th conference of european comparative endocrinologists, Zurich, 21-25 August 2012. - - p. 62 - 62.
Neuroendocrine regulation of leukocyte apoptosis in common carp
Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2012
In: 26th conference of european comparative endocrinologists, Zurich, 21-25 August 2012. - - p. 121 - 121.
Adrenergic regulation of the immune response in common carp
Chadzinska, M.K. ; Kepka, M. ; Verburg-van Kemenade, B.M.L. - \ 2012
In: 26th conference of european comparative endocrinologists, Zurich, 21-25 August 2012. - - p. 63 - 63.
Neutrophil extracellular traps in carp
Pijanowski, L. ; Golbach, L.A. ; Verburg-van Kemenade, B.M.L. ; Kolaczkowska, E. ; Chadzinska, M.K. - \ 2012
In: The 12th congress of ISDCI program and abstracts, Fukuoka, Japan, 9-13 July 2012. - - p. 68 - 68.
Melatonin reduced ROS-dependent apoptosis of carp phagocytes
Kepka, M. ; Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2012
In: The 12th Congress of ISDCI program and abstracts, Fukuoka, Japan, 9-13 July 2012. - - p. 69 - 69.
Phylogenetic and functional diversity of CXC chemokines and their receptors in cyprinids
Chadzinska, M.K. ; Aa, L.M. van der; Golbach, L.A. ; Boudinot, P. ; Verburg-van Kemenade, B.M.L. - \ 2012
In: 12th Congress of ISDCI Program and Abstracts, Fukuoka, Japan, 9-13 July 2012. - - p. 34 - 34.
Diversification of IFNy-inducible CXCb chemokines in cyprinid fish
Aa, L.M. van der; Chadzinska, M.K. ; Derks, W. ; Scheer, M.H. ; Levraud, J.P. ; Boudinot, P. ; Verburg-van Kemenade, B.M.L. - \ 2012
Developmental and Comparative Immunology 38 (2012)2. - ISSN 0145-305X - p. 243 - 253.
trout oncorhynchus-mykiss - chemoattractant i-tac - carpio l. - differential expression - molecular evolution - gene-expression - receptor cxcr3 - early-response - cutting edge - cells
We earlier identified two CXCL8-like lineages in cyprinid fish, which are functional homologues of the mammalian CXCL8, but with diverged functions. We here investigated whether the carp IFN-¿-inducible CXCb gene, related to the mammalian CXCL9, -10 and -11 chemokines, was subject to a similar diversification. On the zebrafish genome, a cluster of seven CXCb genes was found on chromosome five. Analysis of the promoter of the zebrafish CXCb genes suggests a partially shared, but differential induction. A second CXCb gene, CXCb2, was identified in common carp by homology cloning. CXCb2 is constitutively expressed in immune-related tissues, predominantly in head kidney lymphocytes/monocytes. Interestingly, an induction of CXCb2 gene expression with recombinant carp IFN-¿2 and LPS was observed in macrophages and granulocytes. Finally, difference in sensitivity to LPS, and kinetics of CXCb1 and CXCb2 gene expression during zymosan-induced peritonitis, was observed. These results indicate a functional diversification for cyprinid CXCb chemokines, with functional homology to mammalian CXCL9–11.
Pro-inflammatory functions of carp CXCL8-like and CXCb chemokines
Aa, L.M. van der; Chadzinska, M.K. ; Golbach, L.A. ; Ribeiro, C.M.S. ; Verburg-van Kemenade, B.M.L. - \ 2012
Developmental and Comparative Immunology 36 (2012)4. - ISSN 0145-305X - p. 741 - 750.
trout oncorhynchus-mykiss - neutrophil chemotactic factor - interleukin-8 receptors - expression analysis - edwardsiella-ictaluri - molecular evolution - sequence-analysis - gene-expression - gro-alpha - tnf-alpha
Numerous CXC chemokines have been identified in fish, however, their role in inflammation is not well established. Here, CXC chemokines of the CXCL8-like (CXCa_L1 and CXCL8_L2) and CXCL9/10/11-like (CXCb) subset were investigated in carp. Recombinant CXCa_L1, CXCL8_L2 and CXCb all stimulated chemotaxis of macrophages and granulocytes in vitro. CXCb also attracted lymphocytes. Distinct effects on phagocyte activation were observed: the CXCL8-like chemokines increase respiratory burst activity, but not nitrite production. The three chemokines differentially induced a moderate increase in IL-1ß, CXCa_L1 and CXCL8_L2 gene expression. Intracellular calcium mobilization in granulocytes upon CXCa_L1 stimulation implies signal transduction through G-protein coupled CXC receptors. Notably, upon intraperitoneal administration, carp CXCL8-like chemokines strongly induced in vivo leukocyte recruitment, including neutrophils and monocytes/macrophages, in contrast to CXCb, for which the number of recruited leukocytes was low. The results indicate functional homology for carp CXCL8-like and CXCb chemokines with mammalian CXCL8 and CXCL9-11, respectively. --------------------------------------------------------------------------------
Adrenergic regulation of the innate immune response in common carp (Cyprinus carpio L.)
Chadzinska, M.K. ; Tertil, E. ; Kepka, M. ; Hermsen, G.J. ; Scheer, M.H. ; Verburg-van Kemenade, B.M.L. - \ 2012
Developmental and Comparative Immunology 36 (2012)2. - ISSN 0145-305X - p. 306 - 316.
trout oncorhynchus-mykiss - necrosis-factor-alpha - rainbow-trout - beta-adrenoceptors - in-vitro - beta(2)-adrenergic receptor - neutrophilic granulocytes - interleukin-10 production - corticosteroid receptors - catecholamine secretion
Catecholamines exert their physiological actions through a and ß adrenergic receptors (ARs). As ARs are not exclusively expressed on neuroendocrine cells, but also on leukocytes, they may facilitate neuroendocrine modulation of immune responses. We sequenced the ß2a-AR in common carp, and studied its expression profile and involvement in the regulation of teleost innate immune responses. ß2a-AR messenger RNA was found to be constitutively expressed in brain areas, especially in the preoptic nucleus (NPO, homologous to the mammalian hypothalamus), and in immune organs. During the active phase of an in vivo inflammatory response, induced by i.p. zymosan treatment, ß2a-AR gene expression was up-regulated in the peritoneal leukocytes. Additionally, adrenaline in vitro reduced the synthesis of oxygen radical species and nitric oxide, while it enhanced arginase activity in fish phagocytes. Furthermore, in vitro adrenaline administration inhibited expression of pro-inflammatory cytokines, chemokines and their receptors. It is therefore hypothesized that adrenaline will down-regulate phagocyte skewing toward classical/innate polarization.
Neuroendocrine immune interaction in fish: differential regulation of phagocyte activity by neuroendocrine factors
Verburg-van Kemenade, B.M.L. ; Ribeiro, C.M.S. ; Chadzinska, M.K. - \ 2011
General and Comparative Endocrinology 172 (2011)1. - ISSN 0016-6480 - p. 31 - 38.
carp cyprinus-carpio - zebrafish danio-rerio - tilapia oreochromis-niloticus - beta-adrenergic-receptors - trout oncorhynchus-mykiss - delta-opioid receptor - bream sparus-aurata - common carp - functional-characterization - molecular characterization
Coping with physical, chemical and biological disturbances depends on an extensive repertoire of physiological, endocrinological and immunological responses. Fish provide intriguing models to study bi-directional interaction between the neuroendocrine and the immune systems. Macrophages and granulocytes are the main actors in the first and rapid innate immune response. They are resident in different organs and are moreover rapidly recruited and activated upon infection. They act in response to recognition of pathogen-associated molecular patterns (PAMPs) via a repertoire of surface and intracellular receptors by inducing a plethora of defense reactions aiming to eradicate the pathogen. Subsequent production of inflammatory mediators stimulates other leukocytes required to develop an adaptive and specific antibody response. The type of phagocyte reaction will therefore depend on their differentiation state, specific receptor repertoire and their specific location. Apart from these pathogen induced responses, immune reactivity may be modulated by neuroendocrine factors. Over the last years we extensively studied changes in carp stress axis activity and the effect of its end-products on the immune system in an acute stress paradigm. We focus on specific neuroendocrine receptors on leukocytes and their effect on crucial phagocyte activities. We performed identification and functional analyses of different glucocorticoid, opioid and adrenergic receptors on carp phagocytes. Results show that their ligands of neuroendocrine origin may have substantial impact on specific phagocyte functions in a differential way. Inflammatory and microbicidal responses fight pathogens but may be detrimental to the host tissue. Neuroendocrine modulation may regulate inflammation to reach an optimum defense while preventing excessive host cell damage.
Neuroendocrine-immune factors interaction: differential regulation of phagocytic activity in fish by neuroendocrine factors
Verburg-van Kemenade, B.M.L. ; Ribeiro, C.M.S. ; Chadzinska, M.K. - \ 2010
In: Abstract Book 25th Conference of European Comparative Endocrinologists, Pécs, Hungary, 31 August - 4 September 2010. - - p. 40 - 40.
CXCL8 chemokines in cyprinids: two lineages with distinct expression profiles during inflammation
Chadzinska, M.K. ; Aa, L.M. van der; Boudinot, P. ; Verburg-van Kemenade, B.M.L. - \ 2010
In: Abstracts of the First EOFFI Symposium European Organisation of Fish Immunology, Viterbo, Italy, 23-27 May 2010. - - p. 36 - 36.
Trypanosomiasis-induced Th17-like immune responses in carp
Ribeiro, C.M.S. ; Pontes, M.J.S.L. ; Bird, S. ; Chadzinska, M.K. ; Scheer, M.H. ; Verburg-van Kemenade, B.M.L. ; Savelkoul, H.F.J. ; Wiegertjes, G.F. - \ 2010
PLoS ONE 5 (2010)9. - ISSN 1932-6203 - 16 p.
toll-like receptor-2 - toxoplasma-gondii infection - il-12 p40 homodimer - fresh-water fish - cyprinus-carpio - th17 cells - plasmodium-falciparum - dendritic cells - nk cells - signaling pathway
Background - In mammalian vertebrates, the cytokine interleukin (IL)-12 consists of a heterodimer between p35 and p40 subunits whereas interleukin-23 is formed by a heterodimer between p19 and p40 subunits. During an immune response, the balance between IL-12 and IL-23 can depend on the nature of the pathogen associated molecular pattern (PAMP) recognized by, for example TLR2, leading to a preferential production of IL-23. IL-23 production promotes a Th17-mediated immune response characterized by the production of IL-17A/F and several chemokines, important for neutrophil recruitment and activation. For the cold blooded vertebrate common carp, only the IL-12 subunits have been described so far. Methodology/Principal Findings - Common carp is the natural host of two protozoan parasites: Trypanoplasma borreli and Trypanosoma carassii. We found that these parasites negatively affect p35 and p40a gene expression in carp. Transfection studies of HEK293 and carp macrophages show that T. carassii-derived PAMPs are agonists of carp TLR2, promoting p19 and p40c gene expression. The two protozoan parasites induce different immune responses as assessed by gene expression and histological studies. During T. carassii infections, in particular, we observed a propensity to induce p19 and p40c gene expression, suggestive of the formation of IL-23. Infections with T. borreli and T. carassii lead to an increase of IFN-¿2 gene expression whereas IL-17A/F2 gene expression was only observed during T. carasssii infections. The moderate increase in the number of splenic macrophages during T. borreli infection contrasts the marked increase in the number of splenic neutrophilic granulocytes during T. carassii infection, along with an increased gene expression of metalloproteinase-9 and chemokines. Conclusion/Significance - This is the first study that provides evidence for a Th17-like immune response in fish in response to infection with a protozoan parasite
Functional analysis of carp interferon-y: Evolutionary conservation of classical phagocyte acativation
Arts, J.A.J. ; Tijhaar, E. ; Chadzinska, M.K. ; Savelkoul, H.F.J. ; Verburg-van Kemenade, B.M.L. - \ 2010
Fish and Shellfish Immunology 29 (2010)5. - ISSN 1050-4648 - p. 793 - 802.
nitric-oxide synthase - common carp - ifn-gamma - molecular characterization - expression analysis - messenger-rna - tnf-alpha - nf-kb - macrophages - l.
In teleost fish two IFN-¿ gene sequences were found for which two phylogenetic clusters can be distinguished. Our previous analysis of expression of these in carp led us to hypothesize that a classical IFN-¿ function is associated with the IFN-¿2 cluster. We investigated the evolutionary conservation of the IFN-¿ function, inducing classical activation of phagocytes, thus skewing towards a Th1-like profile of immune activation. Recombinant proteins for the carp IFN-¿ sequences of both clusters were made and we studied their effects on expression of proinflammatory mediators. Carp IFN-¿2, in contrast to carp IFN-¿1, was powerful in inducing a proinflammatory reaction in phagocytes: a classical synergistic response with lipopolysaccharide was observed for the induction of iNOS expression and NO release, for expression of CXCL9-11-like chemokines and the expression of proinflammatory cytokines IL-1ß, TNFa and the IL-12 subunits p35 and p40. In contrast, like in mammals, the CXCL8-like cytokines are LPS but not IFN-¿ sensitive. These results corroborate an evolutionary conserved nature of IFN-¿ function in lower vertebrates including classical activation of phagocytes
CXCL8 Chemokines in teleost fish: two lineages with distinct expression profiles during early phases of inflammation
Aa, L.M. van der; Chadzinska, M.K. ; Tijhaar, E. ; Boudinot, P. ; Verburg-van Kemenade, B.M.L. - \ 2010
PLoS ONE 5 (2010)8. - ISSN 1932-6203 - 13 p.
neutrophil-activating factor - trout oncorhynchus-mykiss - cyprinus-carpio l. - interleukin-8 receptors - molecular evolution - chemotactic factor - escherichia-coli - gene-expression - gro-alpha - tnf-alpha
Background - During the inflammatory process, chemokine CXCL8 plays a pivotal role in recruitment of human neutrophilic granulocytes. A diversity of sequences similar to CXCL8 was reported in fish, but their evolutionary relationships and functional homology with their human homolog remain unclear. Principal Findings - We screened fish genomes to seek for sequences related to CXCL8. A first lineage was retrieved in all teleosts, while a second CXCL8 lineage was found in zebrafish and carp only. An early inflammatory function for both lineages was indicated by several lines of evidence. The induction of carp CXCL8s, CXCb, and CXC receptor-1 and -2 was analyzed after in vitro stimulation of leukocyte subpopulations and in two in vivo inflammation models. Recombinant proteins of carp CXCL8 proteins were produced and showed significant chemotactic activity for carp leukocytes. Conclusions - While both carp CXCL8s appear to be functional homologs of mammalian CXCL8, their different induction requirements and kinetics evoke a gene-specific sub-functionalization
Opioids alter cytokine/chemokine profiles during inflammation in fish
Chadzinska, M.K. ; Verburg-van Kemenade, B.M.L. - \ 2009
Function of the opioid system during inflammation in carp
Verburg-van Kemenade, B.M.L. ; Savelkoul, H.F.J. ; Chadzinska, M.K. - \ 2009
In: Trends in Comparative Endocrinology and Neurobiology / Vaudry, H., Roubos, E.W., Coast, G., Vallarino, M., [S.l.] : Wiley-Blackwell - ISBN 9781573316712 - p. 528 - 532.
beta-endorphin - in-vitro - fish - receptors - modulation - leukocytes - innate
The opioid system is involved in modulation of both innate and acquired immune responses, thus altering resistance to a variety of infectious agents. We sequenced and characterized carp opioid receptors (MOR, DOR, and KOR) and found their regulated expression in piscine leukocytes. Moreover, both in vivo and in vitro opioids affect activity of leukocytes and expression of inflammatory molecules, especially chemokines and chemokine receptors. Our data indicate an evolutionary conserved role for the opioid system in immune regulation
The impact of stress on immune regulation
Verburg-van Kemenade, B.M.L. ; Chadzinska, M.K. - \ 2009
Wszechswiat 110 (2009)7. - ISSN 0043-9592 - p. 21 - 25.
Neuroendocrine-immune interactions in teleost fish
Verburg-van Kemenade, B.M.L. ; Stolte, H.H. ; Metz, J.R. ; Chadzinska, M.K. - \ 2009
In: Fish Neuroendocrinology / Bernier, N.J., Van der Kraak, G., Farrell, A.P., Brauner, C.J., Burlington : Academic Press (Fish Physiology 28) - ISBN 9780123746313 - p. 313 - 364.
Cloning of opioid receptors in common carp (Cyprinus carpio L.) and their involvement in regulation of stress and immune response
Chadzinska, M.K. ; Hermsen, G.J. ; Savelkoul, H.F.J. ; Verburg-van Kemenade, B.M.L. - \ 2009
Brain, Behavior, and Immunity 23 (2009)2. - ISSN 0889-1591 - p. 257 - 266.
zebrafish danio-rerio - plasma alpha-msh - beta-endorphin - sequence alignment - met-enkephalin - in-vitro - morphine - expression - inflammation - modulation
In mammals opiate alkaloids and endogenous opioid peptides exert their physiological and pharmacological actions through opioid receptors (MOR, DOR and KOR) expressed not only on neuroendocrine cells but also on leukocytes. Therefore, opioids can modulate the immune response. We cloned and sequenced all three classical opioid receptors (MOR, DOR and KOR) in common carp, and studied changes in their expression during stress and immune responses. Messenger RNA of opioid receptors was constitutively expressed in brain areas, specially in the preoptic nucleus NPO (homologous to mammalian hypothalamus). After exposure to prolonged restraint stress, mRNA levels of MOR and DOR decreased in the NPO and in the head kidney. Increased expression of all studied opioid receptors was observed in the pituitary pars distalis (containing ACTH-producing cells). In immune organs, constitutive but lower expression of opioid receptor genes was observed. During in vivo zymosan-induced peritonitis or after in vitro LPS-induced stimulation, when pro-inflammatory functions are activated, expression of the OR genes in leukocytes was concomitantly up-regulated. Additionally, specific agonists of opioid receptors especially reduced leukocyte migratory properties, manifested by reduced chemotaxis and down-regulated expression of chemokine receptors. Our data indicate an evolutionary conserved role for the opioid system in maintaining a dynamic equilibrium while coping with stress and/or infection.
The immune response differentially regulates Hsp70 and glucocorticoid receptor expression in vitro and in vivo in common carp (Cyprinus carpio L.)
Stolte, H.H. ; Chadzinska, M.K. ; Przbylska, D. ; Flik, G. ; Savelkoul, H.F.J. ; Verburg-van Kemenade, B.M.L. - \ 2009
Fish and Shellfish Immunology 27 (2009)1. - ISSN 1050-4648 - p. 9 - 16.
heat-shock response - rainbow-trout - neutrophilic granulocytes - corticosteroid receptors - macrophage polarization - inflammatory cytokines - trypanoplasma-borreli - handling stress - teleost fish - cortisol
Heat shock or stress proteins and glucocorticoids (cortisol) regulate a sequential pro-inflammatory and anti-inflammatory cytokine expression profile to effectively kill pathogens, whilst minimizing damage to the host. Cortisol elicits its effects through the glucocorticoid receptor (GR) for which Hsp70 and Hsp90 are required as chaperones. In common carp, (Cyprinus carpio) duplicated glucocorticoid receptor genes and splice variants with different cortisol sensitivities exist. We investigated the expression profiles of heat shock proteins Hsp70, Hsc70, Hsp90¿ and Hsp90ß and the three different variants of GR in vitro in and in vivo to define their role in immune modulation. A rapid transient induction of GR1 (a and b) and Hsp70 was seen after LPS treatment in vitro in head kidney phagocytes, whereas cortisol treatment did not affect constitutive or LPS-induced expression of Hsp70 or GR1 expression. In vivo zymosan-induced peritonitis upregulated GR and Hsp70 expression which appears to increase sensitivity for cortisol-induced immune modulation. Indeed, the increased GR and Hsp70 expression correlates with inhibition of both LPS- and zymosan-induced expression of pro-inflammatory cytokines. Infection with the blood parasite T. borreli decreases GR1a expression in thymus, but increases GR2 expression in spleen. Differentially regulated expression of Hsp70 and of glucocorticoid receptor variants with different cortisol sensitivities, underlines their physiological importance in a balanced immune response
Morphine affects the inflammatory response in carp by impairment of leukocyte migration
Chadzinska, M.K. ; Savelkoul, H.F.J. ; Verburg-van Kemenade, B.M.L. - \ 2009
Developmental and Comparative Immunology 33 (2009)1. - ISSN 0145-305X - p. 88 - 96.
opioid receptors - carassius-auratus - cyprinus-carpio - beta-endorphin - in-vitro - peritoneal inflammation - murine macrophages - immune-response - modulation - goldfish
Opioid peptides are evolutionary conserved and in teleost fish their specific receptor types have been identified not only on neuroendocrine cells but also on immunocytes. In the present work we have studied the effects of morphine, ligand for the mu3 opioid receptor, on innate immune responses of common carp. Both in vitro and in vivo, during zymosan-induced peritonitis, morphine reduced gene expression of pro-inflammatory cytokines/chemokines and chemokine receptors. Furthermore, in vitro morphine administration also affects nitric oxide production, chemotaxis and apoptosis of head kidney leukocytes. These results provide evidence for an anti-inflammatory function of morphine and suggest an evolutionary conserved cross-talk between chemokines and opioids
Function for the opioid system during inflammation in teleost fish
Verburg-van Kemenade, B.M.L. ; Savelkoul, H.F.J. ; Chadzinska, M.K. - \ 2008
In: Abstract Book 24th Conference European Comparative Endocrinologists, Genoa, Italy, 2 - 6 September, 2008. - - p. 88 - 88.
In mammals the opioid system is involved in modulation of both innate and acquired immune responses, thus altering resistance to a variety of infectious agents. Opioids can affect immune responses either indirectly, when they stimulate release of cortiocosteroids and/or catecholamines and directly via opioid receptors on leukocytes. Interestingly, specific opioid receptor types have been identified on nonmammalian immunocytes. We have studied the effects of different opioid ligands on innate immune responses of common carp. We sequenced and characterised carp mu, delta and kappa opioid receptors. Moreover, expression profiles of these receptors in different lymphoid organs and specific leukocyte cell populations were studied. In in vitro conditions morphine (agonist of mu3 opioid receptor) reduced gene expression of pro-inflammatory cytokines/chemokines, NO production, chemotaxis and apoptosis of head kidney leukocytes, but did not affect respiratory burst. Furthermore, morphine injected locally to the focus of inflammation during peritonitis reduced the influx of inflammatory leukocytes and downregulated expression of pro-inflammatory mediators (e.g. TNF-a, chemokines, iNOS) and chemokine. Also delta (deltorphine II) and kappa (U50, 488H) opioid receptor agonists modified in vitro leukocyte activity. Our experiments led to the hypothesis that the phylogenetically conserved anti-inflammatory function of opioids includes release of endogenous opioid peptides. Such opioid-dependent modifications of the inflammatory process will be advantageous to the host, because inflammation-related cells and molecules are double-edged nd their high concentration and/or prolonged action may be detrimental.
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