Inhibition of Th1 Differentiation by IL-6 Is Mediated by SOCS1

Diehl, Sean A.; Anguíta, Juan; Hoffmeyer, Angelika; Zapton, Tyler; Ihle, James N.; Fikrig, Erol; Rincón, Mercedes

doi:10.1016/s1074-7613(00)00078-9

Cited by 357 publications

(298 citation statements)

References 55 publications

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“…In this regard, IL-6 was found to inhibit IFN-g receptor-STAT1 signaling-dependent T H 1 differentiation directly through the unregulation of suppressor of cytokine signaling 1 (45). MDSC-induced loss of STAT1 activation in response to IFN-a or IFN-g has been reported in a murine adenocarcinoma model (46), further supporting a link between IFN-g signaling and MDSC-derived IL-6.…”

Section: Discussionmentioning

confidence: 85%

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Tsukamoto

Nishikata

Senju

et al. 2013

Cancer Immunology Research

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Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (T H 1) was significantly attenuated, and impaired T H 1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Furthermore, we found that Gr-1 þ myeloid-derived suppressor cells (MDSC) served as a source of IL-6 in tumor-bearing mice. Adoptive transfer of effector CD4 þ T cells revealed that MDSC-sensitized effector CD4 þ T cells were less potent in mounting antitumor immune responses, although effector T cells generated together with Gr-1 þ cells from tumor-free mice eradicated established tumors. CD8 þ T cells, IFN-g, and MHC-class II expression in host mice were indispensable for the antitumor activity initiated by effector CD4 þ T cells. Despite comparable suppressive activity of IL-6 þ/þ and IL-6 À/À MDSC on primary T-cell activation, transfer of IL-6 þ/þ MDSC, but not IL-6 À/À MDSC, dampened the efficient induction of effector T H 1 cells and counteracted CD4 þ T cell-mediated antitumor immunity including cognate help for CD8 þ T cells in vivo. These findings suggest that, apart from the inhibitory effects on primary T-cell activation, MDSC promote tumor progression by attenuating functional differentiation of tumor-specific CD4 þ T cells into effector T H 1 cells through IL-6 production to promote tumor progression. This novel mode of MDSC-induced tolerance of effector CD4 þ T cells should be considered as the basis for the rational design of effective T cell-mediated antitumor therapies.

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Section: Discussionmentioning

confidence: 85%

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Tsukamoto

Nishikata

Senju

et al. 2013

Cancer Immunology Research

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“…IL-6 has been previously implicated in promoting Th2 differentiation through both IL-4-dependent and -independent mechanisms (33,34). IL-6 can also promote T cell survival (35,36), raising the possibility that limiting amounts of IL-6 might contribute to the arrested phenotype.…”

Section: Resultsmentioning

confidence: 99%

Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint

Mohrs

Lacy

Locksley

2003

The Journal of Immunology

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Activation of naive Th lymphocytes by the TCR and the costimulatory molecule, CD28, is believed to provide competent signals for differentiation to effector cells. Such activated cells proliferated and expressed IL-2, but arrested in an immature state maintained by CTLA-4. Although unresponsive to restimulation by TCR/CD28 alone, restimulation with TCR/CD28 and either Stat4- or Stat6-mediated cytokine signals rescued cells to proliferate and differentiate to the appropriately matched canonical Th subsets. Addition of IL-4 at defined periods revealed that naive T cells were receptive to IL-4-mediated differentiation for up to 3 days after their initial priming. A Stat-dependent anergic checkpoint between clonal expansion and effector cell differentiation may defer the cytokine profile to be instructed at the site of infection, thus preventing the unregulated development of potentially damaging effector cells.

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“…Generally considered as a Th2 cytokine, IL-10 is able to affect Th1/Th2 balance, promote Th2 development, and inhibit Th1 differentiation. It has been shown that inhibition of Th1 differentiation by IL-6 is mediated by SOCS1 (40). It is possible that SOCS1 also plays an important role in regulating Th1/Th2 immune derivation by IL-10, directly inhibiting IFN-␥ signals and Th1 differentiation.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 Inhibits IL-10-Mediated Immune Responses

Ding

Chen

Tarcsafalvi

et al. 2003

The Journal of Immunology

127

108

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IL-10 has proved to be a key cytokine in regulating inflammatory responses by controlling the production and function of various other cytokines. The suppressor of cytokine signaling (SOCS) gene products are a family of cytoplasmic molecules that are essential mediators for negatively regulating cytokine signaling. It has been previously shown that IL-10 induced SOCS3 expression and that forced constitutive expression of SOCS3 inhibits IL-10/STAT3 activation and LPS-induced macrophage activation. In this report, we show that, in addition to SOCS3 expression, IL-10 induces SOCS1 up-regulation in all cell lines tested, including Ba/F3 pro-B cells, MC/9 mast cells, M1 leukemia cells, U3A human fibroblasts, and primary mouse CD4+ T cells. Induction of SOCS molecules is dependent on STAT3 activation by IL-10R1. Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses. Pretreatment of M1 cells with IFN-γ resulted in SOCS1 induction and a reduction of IL-10-mediated STAT3 activation and cell growth inhibition. IL-10-induced SOCS is associated with the inhibition of IFN-γ signaling in various cell types, and this inhibition is independent of C-terminal serine residues of the IL-10R, previously shown to be required for other anti-inflammatory responses. Thus, the present results show that both SOCS1 and SOCS3 are induced by IL-10 and may be important inhibitors of both IL-10 and IFN-γ signaling. IL-10-induced SOCS1 may directly inhibit IL-10 IFN-γ signaling, while inhibition of other proinflammatory cytokine responses may use additional IL-10R1-mediated mechanisms.

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Inhibition of Th1 Differentiation by IL-6 Is Mediated by SOCS1

Cited by 357 publications

References 55 publications

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint

Suppressor of Cytokine Signaling 1 Inhibits IL-10-Mediated Immune Responses

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