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Signaling in Mouse Macrophages: Toll-Like Receptor 2 Stimulation Increases Expression of Dominant-Negative STAT1
by mRNA Stabilization 1
Departments of
*
Molecular Virology, Immunology, and Medical Genetics, and
Microbiology, Ohio State University, Columbus, OH 43210
Mycobacterial infections of macrophages have been shown to inhibit the ability of the macrophage to respond to IFN-
. We previously reported that Mycobacterium avium infection of mouse macrophages decreases IFN--induced STAT1 tyrosine phosphorylation and STAT1 DNA binding. Because macrophages respond to M. avium through Toll-like receptor 2 (TLR2), we determined whether TLR2 stimulation inhibits the response to IFN-. Treatment of mouse RAW264.7 macrophages with TLR2 agonists inhibited the induction of IFN--inducible genes by IFN-. In contrast to M. avium infection, TLR2 agonists did not inhibit the IFN- induction of DNA-binding activity of STAT1 and the tyrosine phosphorylation of STAT1
. Instead, IFN- induction of RAW264.7 cells treated with TLR2 agonists resulted in an increase in the tyrosine phosphorylation of the dominant-negative STAT1
. TLR2 stimulation of RAW264.7 cells increased both STAT1 protein and mRNA expression, suggesting that the increased STAT1 phosphorylation results from increased STAT1 expression. Because STAT1 and STAT1 mRNA have different 3' untranslated regions, and 3' untranslated regions can regulate mRNA stability, we examined the effects of TLR2 stimulation on mRNA stability. TLR2 stimulation of RAW264.7 cells increased the stability of STAT1 mRNA, while not affecting the stability of STAT1 mRNA. The ability of STAT1 to function as a dominant negative was confirmed by overexpression of STAT1 in RAW264.7 macrophages by transient transfection, which inhibited IFN--induced gene expression. These findings suggest that M. avium infection of mouse macrophages inhibits IFN- signaling through a TLR2-dependent increase in STAT1 expression by mRNA stablization and a TLR2-independent inhibition of STAT1 tyrosine phosphorylation.
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