Regulation of immune responses by interleukin-27 (original) (raw)
Related papers
Interleukin 27 signaling pathways in regulation of immune and autoimmune responses
The International Journal of Biochemistry & Cell Biology, 2008
Cytokine-mediated immunity plays a crucial role in pathogenesis of various diseases including autoimmune disease. Recently, interleukin 27 was identified, which along with interleukin 23 belongs to the interleukin 12 cytokine family. Interleukin 27 is pivotal for the induction of T helper 1 responses. Recent studies, however, revealed that interleukin 27 has an immunosuppressive property. In interleukin 27 receptor-deficient mice, various pro-inflammatory cytokines were over produced resulting in excess of immune responses. The immunosuppressive effects of interleukin 27 depend on suppression of interleukin 2 production, inhibition of the development of T helper 17 cells (a newly identified inflammatogenic T helper population), and induction of interleukin 10 production. Activation of signal transducers and activators of transcription 1 and 3 is critical in the immunosuppressive function of interleukin 27. Interleukin 27 suppresses some diseases of autoimmune or allergic origin, demonstrating its promising potential in therapy of diseases mediated by inflammatory cytokines.
PLOS Pathogens, 2015
African trypanosomes are extracellular protozoan parasites causing a chronic debilitating disease associated with a persistent inflammatory response. Maintaining the balance of the inflammatory response via downregulation of activation of M1-type myeloid cells was previously shown to be crucial to allow prolonged survival. Here we demonstrate that infection with African trypanosomes of IL-27 receptor-deficient (IL-27R-/-) mice results in severe liver immunopathology and dramatically reduced survival as compared to wild-type mice. This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4 + T cells and strongly enhanced production of inflammatory cytokines including IFN-γ. What is important is that IL-10 production was not impaired in infected IL-27R-/mice. Depletion of CD4 + T cells in infected IL-27R-/mice resulted in a dramatically reduced production of IFN-γ, preventing the early mortality of infected IL-27R-/mice. This was accompanied by a significantly reduced inflammatory response and a major amelioration of liver pathology. These results could be mimicked by treating IL-27R-/mice with a neutralizing anti-IFN-γ antibody. Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4 + Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes. These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.
The Journal of …, 2006
Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the IL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4 ؉ T cells while it had no effect on the cytokine production by CD4 ؉ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4 ؉ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4 ؉ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4 ؉ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4 ؉ T cells plays an important role in the cytokine suppression by IL-27/WSX-1.
Regulation of defense responses against protozoan infection by interleukin-27 and related cytokines
Journal of biomedicine & biotechnology, 2007
Cytokine-mediated immunity is crucial in the defense against pathogens. Recently, IL-23 and IL-27 were identified, which along with IL-12 belong to the IL-12 cytokine family. IL-27 is pivotal for the induction of helper T cell (Th) 1 responses while IL-23 is important for the proliferation of memory type Th1 cells. Recent studies revealed that IL-27 also has an anti-inflammatory property. In some protozoan infection, various proinflammatory cytokines were over produced causing lethal inflammatory responses in IL-27 receptor-deficient mice. The anti-inflammatory effect of IL-27 depends, at least partly, on inhibition of the development of Th17 cells, a newly identified Th population that is induced by IL-23 and is characterized by the production of the inflammatogenic cytokine, IL-17. IL-27 thus has a double identity as an initiator and as an attenuator of immune responses and inflammation. With the discoveries of the new IL-12-related cytokines and Th17 cells, Th development is faci...
The IL-27R (WSX-1) Is Required to Suppress T Cell Hyperactivity during Infection
Immunity, 2003
T cells and CD8 ϩ T cells (Sprecher et al., 1998; Chen et School of Veterinary Medicine al., 2000; Yoshida et al., 2001). Recent studies have University of Pennsylvania identified IL-27, a heterodimeric cytokine composed of 3800 Spruce St the subunits EBI3 and IL-27p28, as the ligand for WSX-1 Philadelphia, Pennsylvania 19104 (Pflanz et al., 2002). EBI3, a member of the class I cyto-2 DNAX Research Institute kine receptor family, shares significant structural homol-901 California Avenue ogy to IL-12p40, and IL-27p28 is closely related to IL-Palo Alto, California 94304 12p35 (Pflanz et al., 2002). In addition to the structural 3 Department of Inflammation Research similarity between the IL-12/IL-12R and IL-27/WSX-1 Amgen Inc. ligand-receptor pairs, there are also studies that show Thousand Oaks, California 91320 functional parallels. While the IL-12R plays a critical role 4 Division of Molecular and Cellular Immunology in the development of Th1 type responses (Altare et al., Medical Institute of Bioregulation 1998; de Jorg et al., 1998), it has been reported that Kyushu University WSX-1-deficient T cells have impaired IFN-␥ production Maidashi, Higashi-ku, Fukuoka 812-8582 (Chen et al., 2000; Yoshida et al., 2001). Moreover, re-Japan combinant IL-27, like IL-12, can enhance production of PRESTO Japan Science and Technology IFN-␥ by highly purified naive helper T cells (Pflanz et Corporation (JST) al., 2002). As a consequence of these studies, an early Honcho 4-1-8 consensus emerged that IL-27/WSX-1 was, like the IL-Kawaguchi, Saitama, 332-0012 12/IL-12R interaction, an important factor in the initial Japan differentiation of Th1 responses (Robinson and O'Garra, 5 Ontario Cancer Institute and 2002; Ho & Glimcher, 2002; Murphy & Reiner, 2002; Ag-Departments of Medical Biophysics and Immunology nello et al., 2003). University of Toronto Subsequent studies have reported a critical difference Toronto, Ontario M5G2C1 between the IL-27/WSX-1 signaling cascade and that Canada of IL-12/IL-12R. IL-12 can induce tyrosine phosphorylation of STAT1, STAT3, and STAT4 (Trinchieri, 2003), while IL-27 ligation of WSX-1 leads to activation of STAT1 but not STAT4 in CD4 ϩ T cells (Takeda et al., Summary 2003). Though STAT4 plays a critical role in the generation of Th1 responses and both IL-12 and IL-27 can enhance IFN-␥ production, it appears that the two cyto-Although recent studies have described IL-27 and its kines exert this effect through distinct biochemical pathreceptor, WSX-1, as promoters of Th1 differentiation ways. In fact, since naive T cells do not express funcin naive CD4 ؉ T cells, the data presented here indicate tional IL-12 receptor and WSX-1 ligation has been shown that signaling through this receptor is involved in limto enhance IL-12R2 expression through STAT-1iting the intensity and duration of T cell activity. When dependent mechanisms, IL-27 may aid in sensitizing WSX-1-deficient mice are infected with the intracellunaive T cells to the polarizing influences of IL-12 (Takeda lar pathogen Toxoplasma gondii, they establish proet al., 2003). However, as several other cytokines, includtective T cell responses, characterized by production ing IFN-␣ and IFN-␥, can activate STAT-1 and thereby of inflammatory cytokines and control of parasite repenhance expression of IL-12R2, the relative imporlication. However, infected WSX-1 Ϫ/Ϫ mice are unable tance of IL-27/WSX-1 in this process may vary according to downregulate these protective responses, and deto the stimulus and cytokine microenvironment (O'Shea velop a lethal, T cell-mediated inflammatory disease. et al., 2002). This pathology was characterized by the excessive Given the importance of IL-12 and IFN-␥ in resistance production of IFN-␥, persistence of highly activated to intracellular pathogens (Trinchieri, 1998, 2003), experT cells, and enhanced T cell proliferation in vivo. Toiments were performed to determine the role of IL-27/ gether, these findings demonstrate that WSX-1 is not WSX-1 in immunity to Toxoplasma gondii, an obligate required for the generation of IFN-␥Ϫmediated immuintracellular eukaryote that is an important opportunistic nity to this parasitic infection and identify a novel funcparasite of prenatal infants and immunocompromised tion for this receptor as a potent antagonist of T celladults (Denkers and Gazzinelli, 1998). Resistance to this mediated, immune hyperactivity. pathogen is dependent on the development of a strongly polarized, IL-12-dependent, Th1 type response that is characterized by the production of IFN-␥ by NK and CD4 ϩ /CD8 ϩ T cells (Suzuki et al., 1988; Gazzinelli et
The Journal of Immunology, 2006
Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the IL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4 ؉ T cells while it had no effect on the cytokine production by CD4 ؉ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4 ؉ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4 ؉ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4 ؉ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4 ؉ T cells plays an important role in the cytokine suppression by IL-27/WSX-1.
Diverse and Opposing Roles of IL-27 in Immunity
2010
IL-27 was originally thought to play a pro-inflammatory role in immunity, however it is now clear that IL-27 also exerts potent anti-inflammatory effects. Here, we discuss some of the key studies that have elucidated the diverse and apparently paradoxical roles of IL-27. While IL-27 can promote early Th1 development there is evidence of suppressive effects in later phases of Th1 responses. IL-27 exerts a direct inhibitory effect in Th2 immunity by blocking Th2 cell differentiation. The role of IL-27 in Th17 immune responses is also complex as it seems that while IL-27 can block early Th17 development, fully differentiated Th17 cells may become resistant to the inhibitory effects of IL-27. In the field of cancer biology, IL-27 has been shown to have anti-tumourigenic effects however it acts via both immunogenic and nonimmunogenic mechanisms. Collectively, the studies discussed in this review have demonstrated multiple biological functions and mechanisms of action of IL-27. © Fonseca-Kelly et al.; Licensee Bentham Open. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
Frontiers in Immunology, 2016
The complexity of Leishmania-host interactions, one of the main leishmaniasis issues, is yet to be fully understood. We detected elevated IL-27 plasma levels in European patients with active visceral disease caused by Leishmania infantum, which returned to basal levels after successful treatment, suggesting this cytokine as a probable infection mediator. We further addressed this hypothesis recurring to two classical susceptible visceral leishmaniasis mouse models. BALB/c, but not C57BL/6 mice, showed increased IL-27 systemic levels after infection, which was associated with an upregulation of IL-27p28 expression by dendritic cells and higher parasite burdens. Neutralization of IL-27 in acutely infected BALB/c led to decreased parasite burdens and a transient increase in IFN-γ + splenic T cells, while administration of IL-27 to C57BL/6 promoted a local anti-inflammatory cytokine response at the site of infection and increased parasite loads. Overall, we show that, as in humans, BALB/c IL-27 systemic levels are infection dependently upregulated and may favor parasite installation by controlling inflammation.
The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity
The Journal of Immunology, 2004
Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1 ؊/؊ mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4 ؉ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.
Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the IL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4 ؉ T cells while it had no effect on the cytokine production by CD4 ؉ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4 ؉ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4 ؉ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4 ؉ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4 ؉ T cells plays an important role in the cytokine suppression by IL-27/WSX-1.