Neutrophil-dependent inflammation dependent on monosodium urate (MSU)crystal-induced IL-8 expression occurs in gout. MSU crystals activatephagocyte Src family tyrosine kinases and the serine/threonine kinasep70s6k. Thus, using monocytic THP-1 cells, we assessed the potentialfor Src family kinases and p70s6k to mediate MSU-induced IL-8expression. MSU crystals induced phosphorylation of p70s6k and the Srckinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated moreby the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin.PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IκBαand suppressed IκB kinase (IKK) activation and NF-κB binding to theIL-8 promoter, signals that mediate MSU-induced IL-8 expression.Transfection of the native Src inhibitor, C-terminal Src kinase (Csk),also suppressed crystal-induced c-Src, ERK1/2, and IκBαphosphorylation and IL-8 expression. We conclude that Src familytyrosine kinase signaling plays a significant role in MSUcrystal-induced IL-8 expression via stimulation of ERK1/2 pathway andNF-κB activation.