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5-Aminosalicylic acid abrogates T-cell proliferation by blocking interleukin-2 production in peripheral blood mononuclear cells

C Stevens, M Lipman, S Fabry, M Moscovitch-Lopatin, W Almawi, S Keresztes, MA Peppercorn and TB Strom

Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.

The antiinflammatory agent sulfasalazine (SS) is prescribed to treat Crohn's disease, ulcerative colitis and rheumatoid arthritis. Activated T cells are present within diseased mucosal and synovial sites. We tested whether SS or its metabolites 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) inhibited the T-cell activation products interleukin 2 (IL-2) and interleukin 2 receptor alpha-chain (IL-2R alpha). Experiments were performed in phytohemaglutinin- and phorbol ester- stimulated peripheral blood mononuclear cells. Radioactive thymidine and leucine incorporation assayed DNA and protein synthesis, respectively. Enzyme-linked immunosorbent assay and Northern blot analysis measured IL-2 and IL-2R alpha. Lactate dehydrogenase release determined cell viability, and intracellular free calcium was measured by an indole fluorescent indicator. SS and 5-ASA, but not SP, inhibited T-cell proliferation and protein synthesis in phytohemaglutinin- and phorbol ester-stimulated peripheral blood monomuclear cells. 5-ASA (625 microM) markedly reduced culture supernatant IL-2 protein levels by 92% and steady-state IL-2 messenger RNA levels 4.4-fold at 24 and 18 hr, respectively. The supplementation of IL-2 restored T-cell proliferation only in 5-ASA-treated cultures. SS, 5-ASA and SP did not alter intracellular calcium accumulation after mitogenic stimulation. SS and 5-ASA (625 microM) caused 71% and 37% cytotoxicity, respectively, in 72- hr cultures. 5-ASA inhibits T-cell proliferation in part by blocking IL- 2 messenger RNA accumulation and protein production downstream of the rise in cytosolic calcium. Inhibition of IL-2 production is an additional mechanism of action for 5-ASA.

Volume 272, Issue 1, pp. 399-406, 01/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics




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