期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 9, 页码 4898-4906出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1000142
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资金
- National Institutes of Health [NS-50665, NS-57563, NS-50665-05WI, T32-NS-48039]
- National Multiple Sclerosis Society [CA1059-A-13, 3892-A-12]
- National Institutes of Health Pilot and Feasibility [AR-48311]
- National Natural Science Foundation of China [30672163]
- China Scholarship Council [2008622086]
Astrocytes have important physiological roles in CNS homeostasis and serve as a bridge between the CNS and immune system. IL-17 and IL-6 are important in many CNS disorders characterized by neuroinflammation. We examined the role of IL-17 on the IL-6 signaling cascade in primary astrocytes. IL-17 functioned in a synergistic manner with IL-6 to induce IL-6 expression in astrocytes. The synergistic effect involved numerous signaling pathways including NF-kappa B, JNK MAPK, and p38 MAPK. The NF-kappa B pathway inhibitor BAY-11, JNK inhibitor JNKi II, and p38 inhibitor SB203580 suppressed the synergistic effect of IL-6 and IL-17 on IL-6 expression. IL-17 synergized with IL-6 to enhance the recruitment of activated NF-kappa B p65, c-Fos, c-Jun, and the histone acetyl-transferases CREB-binding protein and p300 to the IL-6 promoter in vivo to induce IL-6 transcription. This was accompanied by enhanced acetylation of histones H3 and H4 on the IL-6 promoter. Moreover, we elucidated an important role for suppressor of cytokine signaling (SOCS) 3 in IL-17 enhancement of IL-6 signaling in astrocytes. SOCS3 small interfering RNA knockdown and SOCS3 deletion in astrocytes augmented the synergistic effect of IL-6 and IL-17 due to an enhancement of activation of the NF-kappa B and MAPK pathways. These results indicate that astrocytes can serve as a target of Th17 cells and IL-17 in the CNS, and SOCS3 participates in IL-17 functions in the CNS as a negative feedback regulator. The Journal of Immunology, 2010, 184: 4898-4906.
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