|Lee, Joo Young|
Submitted to: Experimental Biology
Publication Type: Abstract Only
Publication Acceptance Date: 4/2/2005
Publication Date: 4/2/2005
Citation: Lee, J., Youn, H.S., Lemay, D., Lowell, C.A., Hwang, D.H. Src-family tyrosine kinase inhibitor (pp1) suppresses lps-induced expression of inducible nitric oxide synthase mediated through the inhibition of interferon b expression in macrophages. Experimental Biology. Abstract 829.7 (pge A1453) Interpretive Summary:
Technical Abstract: Bacterial lipopolysaccharide (LPS) activates Toll-like recptor (TLR4) leading to expression of inflammatory gene products. Non-receptor type Src-family tyrosine kinases are activated by LPS and associated with CD14, a co-receptor for LPS in monocytes and macrophages. Therefore, we determined the role of Src tyrosine kinases in TLR4 signaling pathways and target gene expression in macrophages using genetic, biochemical, and pharmacological approaches. LPS-induced activation of NFkB and p38 MAPK and expression of inducible nitric oxide synthase (iNOS) were not affected in triple Src kinase knockout macrophages (Lyn-/-,Hck-/-). Neither a kinase-defective nor a constitutively active (CA) Lyn affects NFkB activation induced by LPS or TLR4(CA) in W264.7 cells. These results suggest that deletion of three Src kinases (Lyn, Hck, and Fgr) is not sufficient to abolish all Src kinase activities possibly due to functional redundancy of other Src kinases present in macrophages. Therefore, we used a pan-inhibitor of Src tyrosine kinases to investigate the role of Src kinases in TLR4-induced iNOS expression. A selective inhibitor of Src-family kinases, PP1, suppressed LPS-induced iNOS expression resulting from downregulation of IFNB expression and STAT1 phosphorylation. Together, these results suggest that Src tyrosine kinases regulate TLR4 signaling pathways leading to iNOS expression.