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B Inhibitor on In Vitro Cytokine Production and Collagen-Induced Arthritis1
*
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093; and
Signal Pharmaceuticals, San Diego, CA 92121
NF-
B plays a key role in the production of cytokines in
inflammatory diseases. The effects of a novel T cell-specific NF-B
inhibitor, SP100030, were evaluated in cultured Jurkat cells and in
murine collagen-induced arthritis (CIA). Chemical libraries were
screened for NF-B-inhibitory activity. SP100030, a compound
identified in this process, inhibited NF-B activation in
PMA/PHA-activated Jurkat cells by EMSA at a concentration of 1 µM.
Jurkat cells and the monocytic cell line THP-1 were transfected with an
NF-B promotor/luciferase construct and activated. SP100030 inhibited
luciferase production in the Jurkat cells (IC50 = 30
nM). ELISA and RT-PCR confirmed that IL-2, IL-8, and TNF-
production
by activated Jurkat and other T cell lines were inhibited by SP100030.
However, cytokine expression was not blocked by the compound in THP-1
cells, fibroblasts, endothelial cells, or epithelial cells.
Subsequently, DBA/1J mice were immunized with type II collagen.
Treatment with SP100030 (10 mg/kg/day i.p. beginning on day 21)
significantly decreased arthritis severity from onset of clinical signs
to the end of the study on day 34 (arthritis score, 5.6 ± 1.7 for
SP100030 and 9.8 ± 1.5 for control; p <
0.001). Histologic evaluation demonstrated a trend toward improvement
in SP100030-treated animals. EMSA of arthritic mouse ankles in CIA
showed that synovial NF-B binding was suppressed in the
SP100030-treated mice. SP100030 inhibits NF-B activation in T cells,
resulting in reduced NF-B-regulated gene expression and decreased
CIA. Its selectivity for T cells could provide potent immunosuppression
with less toxicity than other NF-B
inhibitors.
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