A synthetic androstene analogue inhibits collagen-induced arthritis in the mouse
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文摘
Dehydroepiandrosterone (DHEA), a precursor of immune-regulating hormones (IRH) including the androstenes, has attracted much interest over the last several decades because of its many antiaging, metabolic, and immune modulating effects. 5-Androstene-16α fluoro-17-one (fluasterone, also known as HE2500) is a synthetic androstene analogue that retains anti-inflammatory, antiproliferative, and immune-regulating activities of the parent molecule, but is nontoxic and practically devoid of androgenic or estrogenic side effects. In the present studies, we tested the ability of fluasterone to limit disease in the DBA mouse model of collagen-induced arthritis (CIA). We found that mice receiving injections of fluasterone displayed significant delay in onset, decrease in CIA peak score, and significant decrease of the daily mean clinical score. Benefit was associated with significant decreases in (1) bovine type II collagen (bCII)-specific IgG1 and IgG2a antibody levels in serum; (2) production of TNF-α, IL-6, IFN-γ, but not IL-10; (3) lymphocyte proliferative response to bCII protein; and (4) joint inflammation, erosion, and synovial proliferation as judged by histological analysis. This is the first study to report that an IRH can ameliorate ongoing disease in a CIA mouse model with relevance to RA and to correlate that finding with decreases in pro-inflammatory cytokines.