Veterans Affairs Medical Center and Rheumatology-Allergy/Immunology Division, Department of Medicine, University of California, San Diego
Correspondence: Robert Terkeltaub M.D., VASDHCS, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail: rterkeltaub{at}ucsd.edu
Neutrophil-dependent inflammation dependent on monosodium urate (MSU)
crystal-induced IL-8 expression occurs in gout. MSU crystals activate
phagocyte Src family tyrosine kinases and the serine/threonine kinase
p70s6k. Thus, using monocytic THP-1 cells, we assessed the potential
for Src family kinases and p70s6k to mediate MSU-induced IL-8
expression. MSU crystals induced phosphorylation 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
B
and suppressed IB kinase (IKK) activation and NF-B binding to the
IL-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 IB
phosphorylation and IL-8 expression. We conclude that Src family
tyrosine kinase signaling plays a significant role in MSU
crystal-induced IL-8 expression via stimulation of ERK1/2 pathway and
NF-B activation.
Key Words: chemokine • inflammation • leukocyte • gout
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