Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells

Neutrophil-dependent inflammation dependent on monosodium urate (MSU) cryst al-induced IL-8 expression occurs in gout. MSU crystals activate phagocyte Src family tyrosine kinases and the serine/threonine kinase p70s6k. Thus, u sing monocytic THP-1 cells, we assessed the potential for Src family kinase s and p70s6k to mediate MSU-induced IL-8 expression. MSU crystals induced p hosphorylation of p70s6k and the Src kinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated more by the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin. PP1 inhibited crystal-induced phosphorylation of ERK1/2 and I kappaB alpha and suppressed I kappaB kinase (IKK) activatio n and NF-kappaB binding to the IL-8 promoter, signals that mediate MSU-indu ced IL-8 expression. Transfection of the native Src inhibitor, C-terminal S rc kinase (Csk), also suppressed crystal-induced c-Src, ERK1/2, and I kappa B alpha phosphorylation and IL-8 expression. We conclude that Src family ty rosine kinase signaling plays a significant role in MSU crystal-induced IL- 8 expression via stimulation of ERK1/2 pathway and NF-kappaB activation.