The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells.
The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells.
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DOI：
10.4049/jimmunol.1203084
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发表时间：
2013-08-01
期刊：
影响因子：
--
通讯作者：
Lamont RJ
中科院分区：
文献类型：
--
作者：
Wang H;Brown J;Gao S;Liang S;Jotwani R;Zhou H;Suttles J;Scott DA;Lamont RJ
The role of Janus kinase (JAK)-3 in TLR-mediated innate immune responses is poorly understood, although the suppressive function of JAK3 inhibition in adaptive immune response has been well studied. In this study, we found that JAK3 inhibition enhanced TLR-mediated immune responses by differentially regulating pro- and anti- inflammatory cytokine production in innate immune cells. Specifically, JAK3 inhibition by pharmacological inhibitors or specific siRNA, or JAK3 gene knockout resulted in an increase in TLR-mediated production of pro-inflammatory cytokines, while concurrently decreasing the production of IL-10. Inhibition of JAK3 suppressed phosphorylation of PI3 kinase downstream effectors including Akt, mTORC1, GSK3β and CREB. Constitutive activation of Akt or inhibition of GSK3β abrogated the capability of JAK3 inhibition to enhance pro-inflammatory cytokines and suppress IL-10 production. In contrast, inhibition of PI3K enhanced this regulatory ability of JAK3 in LPS stimulated monocytes. At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of STATs that could be attenuated by neutralization of de novo inflammatory cytokines. JAK3 inhibition exhibited a GSK3 activity-dependent ability to enhance phosphorylation levels and DNA binding of NF-κB p65. Moreover, JAK3 inhibition correlated with an increased CD4+ T cell response. Additionally, higher neutrophil infiltration, IL-17 expression, and intestinal epithelium erosion were observed in JAK3 knockout mice. These findings demonstrate the negative regulatory function of JAK3, and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory cytokine production in innate immune cells.
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