Two-Sided Roles of IL-27: Induction of Th1 Differentiation on Naive CD4+ T Cells versus Suppression of Proinflammatory Cytokine Production Including IL-23-Induced IL-17 on Activated CD4+ T Cells Partially Through STAT3-Dependent Mechanism

Yoshimura, Takeru; Takeda, Atsunobu; Hamano, Shinjiro; Miyazaki, Y.; Kinjyo, Ichiko; Ishibashi, Tatsuro; Yoshimura, Akihiko; Yoshida, Hiroki

doi:10.4049/jimmunol.177.8.5377

Cited by 219 publications

(222 citation statements)

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“…However, there is a recent study demonstrating that the suppressive effect of IL-27 in STAT3-deficient CD4 ϩ T cells is significantly lower than that in wild-type cohorts, and it concluded that the preferential activation of STAT3 in fully activated CD4 ϩ T cells plays an important role in the cytokine suppression by IL-27 (22). The results of this article appear to be consistent with the mechanism by which IL-10 induces anti-inflammatory responses through STAT3 in macrophages (21,49,50), but not with the present results.…”

Section: Discussionmentioning

confidence: 99%

“…These results may presumably imply a role of STAT3 in IL-27-induced cell proliferation. In addition, because one of the IL-27R subunits is the common gp130, and IL-27 can activate STAT3 and induce the suppressor of cytokine signaling (SOCS)-3 expression (19,20), the possibility that IL-27 induces anti-inflammatory response in a mechanism similar to the IL-10-induced STAT3-mediated one was discussed previously (21,22). However, the precise role of STAT3 and its molecular mechanism in not only IL-27-induced cell proliferation but also IL-27-induced anti-inflammatory response remain to be elucidated.…”

Section: Stat3 Is Indispensable To Il-27-mediated Cell Proliferation mentioning

confidence: 99%

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STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

Owaki

Asakawa

Morishima

et al. 2008

The Journal of Immunology

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IL-27, a member of the IL-6/IL-12 family, activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130 subunits, resulting in augmentation of Th1 differentiation and suppression of proinflammatory cytokine production. In the present study, we investigated the role of STAT3 in the IL-27-mediated immune functions. IL-27 induced phosphorylation of STAT1, -2, -3 and -5 in wild-type naive CD4+ T cells, but failed to induce that of STAT3 and STAT5 in STAT3-deficient cohorts. IL-27 induced not only proinflammatory responses including up-regulation of ICAM-1, T-box expressed in T cells, and IL-12Rβ2 and Th1 differentiation, but also anti-inflammatory responses including suppression of proinflammatory cytokine production such as IL-2, IL-4, and IL-13 even in STAT3-deficient naive CD4+ T cells. In contrast, IL-27 augmented c-Myc and Pim-1 expression and induced cell proliferation in wild-type naive CD4+ T cells but not in STAT3-deficient cohorts. Moreover, IL-27 failed to activate STAT3, augment c-Myc and Pim-1 expression, and induce cell proliferation in pro-B BaF/3 transfectants expressing mutant gp130, in which the putative STAT3-binding four Tyr residues in the YXXQ motif of the cytoplasmic region was replaced by Phe. These results suggest that STAT3 is activated through gp130 by IL-27 and is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. Thus, IL-27 may be a cytokine, which activates both STAT1 and STAT3 through distinct receptor subunits, WSX-1 and gp130, respectively, to mediate its individual immune functions.

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Section: Discussionmentioning

confidence: 99%

Section: Stat3 Is Indispensable To Il-27-mediated Cell Proliferation mentioning

confidence: 99%

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

Owaki

Asakawa

Morishima

et al. 2008

The Journal of Immunology

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“…Several papers described the IL-12-independent induction of Th1 cells via IL-27-dependent activation of STAT-1 and T-bet [37]. IL-27 is also involved in the inhibition of Th17 development [38], which could explain the absence of IL-17 increase, although DCs matured with PL-MSCs produced more IL-23 [39]. In line with these results, we showed recently that IL-27 is expressed highly in symptomatic PLs, and that the exogenous IL-27 can stimulate Th1 and down-regulate Th17 cytokines' production by the PL-inflammatory cells [40].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte‐derived dendritic cells

et al. 2013

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Immunoregulatory mechanisms within periapical lesions (PLs) are as of yet unexplored. Considering the crucial role of DCs in controlling the immune response within PLs, the immunomodulatory properties of mesenchymal stem cells (MSCs), and the colocalization of MSCs and DCs in situ, we wondered whether MSCs from PLs modulate the development and functions of DCs. Using a model of monocyte-derived DCs, we showed that PL-MSCs inhibited differentiation of DCs via soluble factors, of which IL-6 had a minor effect, but did not impair their subsequent maturation induced by pro-inflammatory cytokines. However, upon maturation such DCs favored the production of Th2/Th17 cytokines by allogenic CD4 + lymphocytes in coculture, compared with mature DCs differentiated without PL-MSCs. PL-MSC-differentiated DCs, cultivated with pro-inflammatory cytokines and PL-MSCs, although phenotypically mature, exhibited poor allostimulatory activity, induced anergy, Th2 polarization, differentiation of suppressive CD4 + CD25 high CD39 + Treg-cell subsets via IDO-1-, ILT-3-, and ILT-4-dependent mechanisms, and increased production of TGF-β in the coculture. In contrast, DCs cultivated with PL-MSCs only during maturation stimulated proliferation and Th1 polarization of CD4 + T cells in an IL-12-independent manner. In conclusion, PL-MSCs significantly modulate the development and functions of DCs, depending on the phase of DCs development during which the interaction occurs. Keywords: Dendritic cells r Mesenchymal stem cells r Periapical lesions r Th polarizationAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPeriapical lesions (PLs) are a common pathology within the human population initiated by the bacterial invasion of the root canal and develop from an acute inflammatory response to the formation of granulomas or cysts infiltrated by various inflammatory cells [1].Correspondence: Prof. MiodragČolić e-mail: fakultet.vma@mod.gov.rs Furthermore, cytokines produced by Th cells have been shown to play a crucial role in PLs pathogenesis. Namely, Th1-and Th17-derived cytokines promote inflammation, bone resorption, and disease progression. Th2 cells seem to be important for the later phases of PLs development, whereas IL-10 and TGF-β produced by Treg cells seem to be important for the healing processes within PLs [2,3]. However, it is not yet clear which mediators and cells are involved crucially in the regulation of Th-cell commitment during the development, maintenance, and resolution of the disease.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1862-1872 Immunomodulation 1863DCs are the key regulatory and decision-making cells with a unique ability to activate naive T cells and polarize their development. These cells can be differentiated in vitro from monocytes or CD34 + -progenitors with GM-CSF and IL-4, generating CD1a + CD14 − immature DCs (iDCs) [4]. Alternatively, in the absence of IL-4, GM-CSF induces the differ...

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“…We also noted that despite eliciting strong IL-10 induction in the primary stimulation of T cells, IL-27 by itself was not sufficient to promote the formation of a stable, IL-10 producing Th cell lineage (not shown). Indeed, others have demonstrated that IL-27 suppresses IL-10 production upon repeated stimulation, while it caused induction of IL-10 production in FACS-purified naive T cells (13).…”

Section: Il-27 Induces Il-10 Expression By Cd4 ϩ and Cd8 ϩ T Cellsmentioning

confidence: 99%

Cutting Edge: IL-27 Is a Potent Inducer of IL-10 but Not FoxP3 in Murine T Cells

Batten

Kljavin

et al. 2008

The Journal of Immunology

191

167

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The cytokine IL-27 is important for restricting inflammation in response to a wide variety of immune challenges. In this study, we demonstrate that IL-27 induces expression of the anti-inflammatory cytokine IL-10 by CD4+ and CD8+ T cells. IL-27 relied upon the Th1 transcription factor STAT1 to induce IL-10+IFN-γ+FoxP3− Th1 cells, which were recently shown to be key negative regulators during certain infections. Il27ra−/− mice generated fewer IL-10+ T cells during both Listeria monocytogenes infection and experimental autoimmune encephalomyelitis. The data presented here indicate a novel mechanism for the induction of IL-10 expression by T cells and provide a mechanistic basis for the suppressive effects of IL-27.

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Two-Sided Roles of IL-27: Induction of Th1 Differentiation on Naive CD4+ T Cells versus Suppression of Proinflammatory Cytokine Production Including IL-23-Induced IL-17 on Activated CD4+ T Cells Partially Through STAT3-Dependent Mechanism

Cited by 219 publications

References 50 publications

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte‐derived dendritic cells

Cutting Edge: IL-27 Is a Potent Inducer of IL-10 but Not FoxP3 in Murine T Cells

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