Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1.

Abstract

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell-specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4+ T cells produced more transforming growth factor (TGF)-beta1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-beta1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-beta1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-beta1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-beta1 and IL-10 through modulating STAT3 activation.

• Authors: Ichiko Kinjyo, Hiromasa Inoue, Shinjiro Hamano, Satoru Fukuyama, Takeru Yoshimura, Keiko Koga, Hiromi Takaki, Kunisuke Himeno, Giichi Takaesu, Takashi Kobayashi, Akihiko Yoshimura
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 203 Issue 4 Pg. 1021-31 (Apr 17 2006) ISSN: 0022-1007 [Print] United States
• PMID: 16606674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STAT3 Transcription Factor
• Socs3 protein, mouse
• Stat3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Tgfb1 protein, mouse
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Interleukin-10

Topics

• Animals
• Cell Differentiation (immunology)
• Down-Regulation (immunology)
• Interleukin-10 (biosynthesis)
• Leishmania major (immunology)
• Leishmaniasis, Cutaneous (genetics, immunology, metabolism)
• Mice
• Mice, Knockout
• Promoter Regions, Genetic
• STAT3 Transcription Factor (metabolism, physiology)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (deficiency, genetics, physiology)
• T-Lymphocytes, Helper-Inducer (cytology, immunology, metabolism)
• Th2 Cells (immunology, metabolism)
• Transforming Growth Factor beta (biosynthesis, genetics)
• Transforming Growth Factor beta1
• Up-Regulation (genetics, immunology)