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TLR2- and TLR4-dependent activation of STAT1 serine phosphorylation in murine macrophages is protein kinase C--independent

Division of Pulmonary and Critical Care Medicine and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA

Matthew J. Fenton

Division of Pulmonary and Critical Care Medicine and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA, fentonm{at}niaid.nih.gov

Engagement of Toll-like receptor (TLR) proteins activates multiple signal transduction pathways. Previous studies demonstrated that TLR2 and TLR4 engagement leads to rapid phosphorylation of the transcription factor STAT1 at serine 727 (Ser-727 STAT1) in murine macrophages. Only TLR4 engagement induced STAT1 phosphorylation at tyrosine 701, although this response was delayed compared with Ser-727 STAT1 phosphorylation. Unlike other cell types, the p38 mitogen-activated protein kinase was necessary, but not sufficient, for TLR-induced phosphorylation of Ser-727 STAT1 in macrophages. We and others had previously shown that Ser-727 STAT1 phosphorylation could be blocked by rottlerin, an inhibitor of protein kinase C- (PKC—). Here we report that peritoneal exudate macrophages from PKC--deficient mice can be activated through TLR2 and TLR4 to elicit rapid phosphorylation of Ser-727 STAT1, which was blocked by both rottlerin and the p38 inhibitor SB203580, but not by the pan-PKC inhibitor bisindoylmaleamide. Furthermore, both normal and PKC--deficient macrophages secreted comparable amounts of IL-6, IP-10, and RANTES following TLR engagement. In contrast, IFN--induced STAT1 serine phosphorylation was independent of both PKC- and p38. Overall, these studies demonstrate that a PKC-independent signaling pathway downstream of both TLR2 and TLR4 is necessary for Ser-727 STAT1 phosphorylation in primary murine macrophages.

Key Words: TLR4 • TLR2 • signal transduction • interferon

Journal of Endotoxin Research, Vol. 12, No. 4, 231-240 (2006)
DOI: 10.1177/09680519060120040401


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