Regular articleDIFFERENTIAL REGULATION OF INTERLEUKIN 4 AND INTERLEUKIN 13 PRODUCITON BY INTERFERON α
Abstract
Interferon α (IFN-α) has proven its clinical usefulness in a variety of diseases of diverse pathogenesis. In addition to direct antiviral effects, recent evidence suggests that its interaction with the cytokine cascade might contribute to its mechanism of action. This study was undertaken to determine whether IFN-α influences the synthesis of interleukin 4 (IL-4) and IL-13, two cytokines which share many biological properties on various cells and tissues and which have a profound role in regulating immunological and inflammatory responses. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were stimulated with Concanavalin A (ConA), phorbol myristate acetate (PMA), anti-CD3/CD28 mAbs, either alone or in various combinations, and incubated with increasing concentrations of IFN-α. IL-4 and IL-13 mRNA was determined by Northern hybridizations and IL-4 and IL-13 protein synthesis was evaluated by specific enzyme-linked immunosorbent assay (ELISA). IFN-α led to a profound decrease of IL-13 mRNA expression after an incubation period of 5 h with ConA alone or in combination with PMA, whereas it showed no regulatory effect on IL-4 mRNA expression. After an incubation period of 24 h, the decrease in IL-13 mRNA expression after addition of IFN-α was even more pronounced. At the protein level, IFN-α increased IL-4 synthesis dose dependently regardless of the mode of activation. This increase was most pronounced after stimulation with ConA or anti-CD28/PMA. In contrast, IL-13 synthesis was strongly downregulated by IFN-α in a dose-dependent manner irrespective of the activating agent. It is concluded that IL-4 and IL-13, although showing similar biological effects, are differentially regulated by IFN-α.
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The role of interleukin-13 in chronic inflammatory intestinal disorders
2019, Autoimmunity ReviewsCitation Excerpt :The expression and pathway of IL-13 are regulated at different levels. Its transcription and production are positively regulated by both GATA3 and the hedgehog pathway, whereas they are negatively regulated by interferon (IFN)-α [18]. Additionally, the IL-13Rα2 receptor can be considered as a negative regulator of IL-13 pathway, as its transcription is induced by IL-13 itself or IFN-γ, thus leading the receptor from intracellular locations to cell surface [10,19,20].
Interleukin (IL)-13 is a cytokine playing a pivotal role in T helper (Th)2 immune response supposed to be implicated in some intestinal disorders. IL-13 is produced by Th2 cells, natural killer T cell, innate lymphoid cells and innate immune cells, which contribute to trigger and maintain a chronic idiopathic intestinal inflammation. In murine models IL-13 exerts pleiotropic functions, playing either pathogenic or protective roles according to the different experimental conditions. As regards celiac disease, IL-13 is considered to be involved mostly in the refractory phase rather than at uncomplicated stage. Discrepancies have been observed in the role of IL-13 upon the inflammation and fibrosis in ulcerative colitis (UC) and in Crohn's disease, respectively. Failure of the anti-IL-13 monoclonal antibodies tralokinumab and anrukinzumab in UC patients in clinical trials support the absence of a role for IL-13 in UC.
This review deals with IL-13 in several experimental colitis models -such as oxazolone-, trinitrobenzene sulfonic acid- or dextran sodium sulphate-induced colitis- and chronic intestinal inflammatory disorders -including celiac disease, UC and Crohn's disease-, and it also highlights the attempts to modulate IL-13 as therapeutic tool.
Interferon-alpha controls IL-17 expression in vitro and in vivo
2008, ImmunobiologyThe type I interferons interferon alpha (IFNα) and IFNβ are the first line of defense potently induced upon viral infection, and at the same time are immunomodulatory cytokines bridging innate and adaptive immunity. T cells secreting interleukin-17 (IL-17) have recently been identified to regulate neutrophil-mediated inflammation, and have been implicated in the pathogenesis of experimental colitis and human inflammatory bowel disease, and are considered to regulate the inflammatory response in these models. We therefore hypothesized that type I IFNs as sentinels of viral infection might counteract the development of Th17 cells. We studied the effects of IFNα on IL-17 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) and during differentiation of human and murine naïve T cells into Th17 cells. In patients with ulcerative colitis (UC) treated systemically with IFNα, we studied colonic expression of IL-17 before and 4 weeks after therapy. IFNα potently suppressed IL-17 production in PBMC both at the mRNA and protein level. Th17 differentiation of human and murine naïve T cells was markedly suppressed in the presence of IFNα. UC patients exhibited increased IL-17 expression in colonic tissue biopsies compared to healthy controls, which was down-regulated during IFNα therapy. IL-17 expression in colonic tissue correlated with clinical remission in these patients. Our data suggest that IFNα down-regulates IL-17 expression and Th17 differentiation in vitro and in vivo. As a corollary, these effects might play a role in the mode of action of type I IFNs in the treatment of various diseases.
Although pegylated interferon alpha (PEG-IFN-α) with ribavirin treatment constitutes an effective means of treatment for chronic hepatitis C, novel approaches are needed due to the inefficient effects of the current therapy against chronic infection with genotype 1 virus. In this study, the immunomodulatory effects of PEG-IFN-α on multigenic HCV DNA vaccine-induced immunity were investigated in African green monkeys. Multigenic HCV DNA vaccination with and without PEG-IFN-α was safe and well tolerated, and induced significant long-term T cell and antibody responses. In addition, the induced immune responses were gradually increased by repeated injection. Interestingly, co-treatment with PEG-IFN-α significantly suppressed HCV DNA vaccine-induced T cell responses, but not antibody responses, which demonstrated that IFN-α could act as a negative regulator of T cell immune induction. However, the suppression of T cell responses by PEG-IFN-α could be overcome by two times more DNA vaccination, which suggests that combined therapy of DNA vaccine with PEG-IFN-α might be possible. Our results provide valuable information for the design of an effective therapeutic regimen to treat chronic HCV infection and to understand the immunomodulatory roles of PEG-IFN-α in immune induction by DNA vaccination.
L’infection par le virus de l’hépatite C (VHC) a une prévalence évaluée à 1,2 % de la population française dont 80 % sont porteurs chroniques du virus, avec comme principale complication d’un tel état la survenue d’une cirrhose dans 15 à 20 % des cas dans un délai moyen de 15 à 20 ans. L’association de l’interféron α (IFNα) à la ribavirine est actuellement le traitement de référence de l’hépatite chronique C. Le bénéfice thérapeutique se fait au prix de nombreux effets indésirables liés classiquement à l’IFNα. En particulier, les troubles thymiques représentent la cause la plus fréquente de diminution (et d’arrêt) de traitement. Nous nous proposons dans cet article d’exposer : 1) les éléments de discussion sur la question de l’imputabilité des troubles thymiques induits par l’IFNα lors du traitement de l’hépatite C chronique ; 2) les différentes hypothèses élaborées pour éclairer leur physiopathologie. Imputabilité des troubles thymiques à l’IFNα : les principales sources d’équivoque en matière d’imputabilité de la dépression à l’IFNα sont, d’une part, que l’infection par le VHC s’accompagne d’une prévalence accrue de la dépression, et ceci en dehors de tout traitement antiviral et que, d’autre part, le taux de contamination dans les populations psychiatriques est plus élevé que dans la population générale. Ce dernier point est compréhensible aisément pour les usagers de drogues par voie veineuse mais est plus inattendu en cas de d’abus ou de dépendance d’alcool, d’atteinte alcoolique hépatique, d’hospitalisation pour retard mental, psychose ou démence, ou de psychotraumatisme. Malgré ces éléments confondants, l’imputabilité de troubles thymiques à l’IFNα lui-même repose sur des données nombreuses et variées. Tout d’abord, l’IFNα appartient à une famille de molécules, les cytokines, qui sont tenues pour responsables de la plupart des symptômes physiques et psychiques liés à l’infection et l’inflammation. Ensuite, de nombreuses équipes ont rapporté la survenue de manifestations psycho-comportementales chronologiquement consécutives au traitement IFNα : labilité émotionnelle (11 %), anxiété (14 %), irritabilité (32 %), difficultés de concentration (18 %), troubles du sommeil (37 %) et dépression (34 %), idées suicidaires (1,2 %), passages à l’acte suicidaires et troubles psychotiques aigus (épisodes délirants hallucinatoires ou interprétatifs sur terrain prédisposé). La fréquence des troubles thymiques est très variable, allant de 0 à 37 %. Cette variabilité peut être expliquée par l’hétérogénéité : 1) des posologies et des durées de traitements par interféron, 2) des populations de patients acceptés dans les protocoles thérapeutiques, notamment des critères d’exclusion relatifs à l’état psychiatrique ou à l’abus de substances, et 3) des méthodes d’évaluation de la dépression. Physiopathologie : tout d’abord, la nature des symptômes psycho-comportementaux peut être discutée, certains auteurs voyant dans certains d’entre eux (baisse de l’humeur, déficit mnésique, ralentissement cognitif et altération des fonctions exécutives) les stigmates d’une légère démence frontale sous-corticale, telle qu’on peut en rencontrer dans des affections neurologiques (maladie de Parkinson, par exemple). Cette hypothèse est appuyée par certains travaux mettant en évidence des signes d’encéphalopathie a minima. Par ailleurs, les effets comportementaux de l’IFNα ont été reliés à d’autres mécanismes tels que la douleur, la libération d’opioïdes centraux ou le stress aigu. Cependant, la nature thymique des troubles induits par l’IFNα demeure la plus largement admise dans la littérature. Dans ce cadre, l’étude de la physiopathologie des troubles s’avère relativement complexe et aboutit à des conclusions questionnant les théories classiques de la dépression. Dans une perspective dynamiste de la maladie, le trouble dépressif majeur est alors vu comme la conséquence d’une réponse comportementale inappropriée vis-à-vis d’un état de « malaise », lui-même engendré par une activation immunitaire incluant des anomalies du système des cytokines. L’induction de troubles thymiques sous IFNα serait un exemple particulier de ce mécanisme. Quoi qu’il en soit, il est à noter que l’IFNα exogène utilisé en thérapie est un polypeptide qui ne passe pas la barrière hémoméningée saine. Il est donc nécessaire d’envisager la possibilité d’un mécanisme périphérique intermédiaire: activation d’une cascade de production d’autres cytokines endogènes capables d’une action centrale, ou d’une enzyme hépatique impliquée dans le métabolisme de précurseurs de la sérotonine, neuromédiateur majeur dans les théories monoaminergiques de la dépression. Il a ainsi été montré que le traitement par IFNα provoque une modification des taux sériques de tryptophane, acide aminé précurseur de la sérotonine, une diminution des taux du principal métabolite de la sérotonine (le 5-HIAA) dans le LCR et une altération des récepteurs sérotoninergiques centraux. De plus, les antidépresseurs inhibiteurs sélectifs du transporteur de la sérotonine sont actifs pour traiter ou prévenir l’apparition de dépression sous IFNα. Dans une étude récente, les variations des concentrations de tryptophane, de sérotonine et de kinurénines (voie accessoire de catabolisme du tryptophane) ont été corrélées significativement aux scores obtenus à l’échelle dépression MADRS. En ce qui concerne les autres systèmes monoaminergiques, l’IFNα semble avoir un effet amphétamine-like transitoire suivi d’une diminution du tonus dopaminergique en administration chronique. L’IFNα entraîne également des modifications du système noradrénergique. Enfin, des hypothèses neuroendocriniennes ont été formulées. Conclusion – La conduite à tenir devant les troubles thymiques sous IFNα doit prendre en compte 3 ordres de faits : une relative dose-dépendance, une sensibilité satisfaisante aux ISRS, et ses relations possibles avec la symptomatologie physique. Il est ainsi possible de prévenir ou traiter les troubles thymiques en se basant sur ces éléments : baisse des posologies, fenêtres thérapeutiques, prescription d’ISRS, attention particulière aux symptômes physiques et systématisation de leur traitement préventif. Par ailleurs, dans une perspective de santé publique, ceci devrait contribuer à achever de convaincre les cliniciens de la légitimité de pas écarter les patients dits « à risque » mais de les manager de façon pragmatique et prudente.
Imputability of thymic disorders caused by IFNα during the chronic Hepatitis C treatment – hepatitis C and depression – The infection by the hepatitis C virus (HCV) is a major public health concern since it affects 1.2 % in the French population. Eighty percent of those contaminated by HCV keep bearing the virus chronically although they remain asymptomatic during many years. HCV infection is associated with psychiatric symptoms like depression. Together with other factors (eg the severity of hepatic condition), depression may induce significant impairment in quality of life. Conversely, some psychiatric conditions may increase the risk of HCV infection. In drug-addicted subjects using intravenous route, HCV contamination rate ranges from 74 to 100 %. Compared with general population, a higher HCV contamination rate has also been noticed in some other subgroups of subjects (patients with alcohol abuse or dependence, with alcohol-induced hepatic disease and psychiatric inpatients). However, no valid explanation to this phenomenon has been established. Interferon α and depression – Interferons are a variety of cytokines naturally produced by human tissues and have also been synthesized for therapeutic purposes (treatment of a variety of cancers and viral infections). Many psychobehavioural symptoms are observed under IFNα treatment. Among them, mood disorders are known to occur early after entry into treatment and to be within the reach of preventive measures. The reported frequency of depression during IFNα treatment ranges from 0 to 37 %. This variation reflects either methodological biases (eg differences in psychiatric assessment) or the heterogeneity of the population of patients accepted in therapeutic protocols. Note that the adjunction of ribavirine to IFNα in therapeutic protocols has not brought any changes in the depression frequency. The causal relationship between IFNα administration and the occurrence of mood disorders has been tackled by various recent research works focusing on the importance of the immune system in the pathophysiology of depression. Miscellaneous pathophysiological hypotheses – nature of the psychobehavioural symptomatology – In addition to depressive symptoms, IFNα treatment also induces various cognitive impairments and disruptions in EEG patterns. These symptoms are consistent with a mild subcortical dementia. Data resulting from pharmacological trials in humans and in animals are controversial (eg IFNα-induced symptoms being alleviated by both immune and antidepressant therapies). However, the debate about the nature of the psychobehavioural disorders observed under IFNα treatment might be no longer relevant in the light of recent theories which regard depression as a maladaptive response to a particular form of stress, namely a deep and diffuse feeling of sickness (« malaise »). These theoretical views ascribe the production of depressive symptoms to a disruption in the immune function, mediated by the variety of cytokines. The therapeutic effects of anti-depressive drugs are thus attributed to their analgesic properties, reducing the « malaise » feeling underlying depressive symptoms. Necessity of a second messinger – Accordingly to current pathophysiological theories, depression results from disorders of various CNS functions, mainly limbic, monaminergic and neuroendocrinal systems. Though, exogenous IFNα does not cross the blood-brain barrier when unscathed and an intermediary mechanism is necessary. First to be addressed is the cytokines system itself since it is composed of numerous different molecules interacting in an infinite number of possible combinations. Some of these cytokines (eg some interleukins) both are activated by IFNα and can reach CNS ; they are good candidates for the role of second messenger mediating the induction of psychobehavioural disorders. Second, keeping in mind that serotonin is a monoaminergic neurotransmitter classically involved in depression pathophysiology, other works have demonstrated that IFNα modulates the peripheral activity of indolamine dioxygenase - a regulating enzyme of serotonin metabolism – possibly through lymphocyte T CD4 activation. Third, other authors have postulated an immune-induced vagal mechanism to explain depression caused by IFNα. Action of IFNα on the neuroendocrine and on neuromodulating functions : monoaminergic hypothesis – Cytokines could have an influence on the mood through their modulating role on the serotoninergic system. IFNα treatment is reported to produce : 1) a decrease in trytophan availability for serotonin synthesis, 2) a decrease in the 5-HIAA level in the LCR, and 3) a modification of the central serotoninergic receptors. Moreover, selective inhibitors of serotonin transporters are effective to treat or prevent depression caused by IFNα. Many studies support the serotonin-transporter hypothesis : in vitro, both IFNα and interleukine 4 (IL-4) increases the expression of serotonin transporter gene, IFNα increases in the production of IL-4 by mononucleus cells (not found in vivo). Serotoninergic system can also be altered by a peripheral action of IFNα on trytophan catabolism by activating a concurrent pathway (known as « kynurenine pathway») to serotonin synthesis. Finally, serotonin-mediated vulnerability to the psycho-behavioural effects of IFNα could be underlain by a polymorphism of serotonin transporter gene. Concerning the other monoaminergic systems, IFNα seems to have an amphetamine-like effect at its first administration, followed by a decrease in dopaminergic tone with chronic administration. Dopaminergic depletion, subsequent to psychostimulant abuse for instance, results in severe depressive syndromes. Interactions between IFNα and noradrenergic system have also been reported. Neuroendocrinian hypothesis – When administered through central or peripheral way, IFNα simulates/inhibits the corticotrope axis and alters endorphin system as shown by the induction of analgesia, catatonia and behavioural slowdown that can be suppressed by opioid antagonists. IFNα neurotoxic effects are successfully treated by naltrexone. Lastly, IFNα is known to cause disorders in thyroid function that are likely to contribute to the production or aggravation of mood disorders. Conclusion – A better understanding of pathophysiologic mechanisms underlying psychiatric side effects of IFNα is essential to extend access to treatment to some categories of patients that remain excluded from the protocols. A better management of those psychiatric side effects should help the clinician not to draw aside patients at risk, ie patients with depression, drug and alcohol addiction. Treating them in a pragmatic and careful way is a major issue, since this population represents a high percentage of the potential candidates for interferon therapy.
Interleukin-6 stimulates thrombopoiesis through thrombopoietin: Role in inflammatory thrombocytosis
2001, BloodCitation Excerpt :Specific PCR products were purified using NucleoSpin Extract (Macherey-Nagel, Düren, Germany). The probes were radioactively labeled with [32P]dCTP using the random primed labeling method according to the manufacturer's (Roche) instructions and hybridized as described.32 Control hybridizations were performed with β-actin to ensure equal loading of RNA.
Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6–treated cancer patients. It is shown that IL-6–induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6–induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.
Diagnostic and treatment methods for ulcerative colitis and colitis-associated cancer
2021, Diagnostic and Treatment Methods for Ulcerative Colitis and Colitis-Associated Cancer
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Correspondence to: Herbert Tilg, Department of Medicine, University Hospital Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria