Cytokine production by innate immunity is critical for shaping the adaptive immunity through regulation of T cell differentiation. In this report, we studied T cell immunoglobulin mucin domain protein 3 (Tim-3) expression on monocytes and its regulatory effect on interleukin-12 (IL-12)/IL-23 production by CD14+ monocytes, as well as IL-17 production by CD4+ T cells in individuals with chronic hepatitis C virus (HCV) infection. We found that Tim-3 and IL-23p19 are highly expressed and that IL-12p35 is inhibited in human CD14+ monocytes, while IL-17 expression is upregulated in CD4+ T cells, in chronically HCV-infected individuals compared to healthy subjects. Interestingly, Tim-3 expression is closely associated with the differential regulation of IL-12/IL-23 expression in CD14+ monocytes and correlated to IL-17 production by CD4+ T cells. These Tim-3- associated IL-12/IL-23/IL-17 dysregulations in HCV-infected individuals are also recapitulated in vitro by incubating healthy monocytes or peripheral blood mononuclear cells with Huh-7 hepatoma cells transfected with HCV RNA. Importantly, blocking Tim-3 signaling on monocytes restores the balance of IL-12/IL-23 through the intracellular STAT3 signaling, which in turn reverses the upregulated IL-17 expression both ex vivo and in vitro. Our findings suggest that Tim-3-mediated differential regulation of IL-12/IL-23 drives TH17 cell development, a milieu favoring viral persistence and autoimmune phenomenon during HCV infection.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etsu-works-15569 |
| Date | 01 April 2013 |
| Creators | Wang, Jia M., Shi, Lei, Ma, Cheng J., Ji, Xiao J., Ying, Ruo S., Wu, Xiao Y., Wang, Ke S., Li, Guangyu, Moorman, Jonathan P., Yao, Zhi Q. |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | ETSU Faculty Works |
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