Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expression

The anti-inflammatory agent sulphasalazine is an important component of sev eral treatment regimens in the therapy of ulcerative colitis, Crohn's disea se and rheumatoid arthritis. Sulphasalazine has many immunomodulatory actio ns, including modulation of the function of a variety of cell types, such a s lymphocytes, natural killer cells, epithelial cells and mast cells. Howev er, the effect of this agent on macrophage (M phi) function has not been ch aracterized in detail. In the present study, we investigated the effect of sulphasalazine and two related compounds - sulphapyridine and 5-aminosalicy lic acid - on M phi activation induced by bacterial lipopolysaccharide (LPS ) and interferon-gamma (IFN-gamma). In J774 M phi stimulated with LPS (10 m ug/ml) and IFN-gamma (100 U/ml), sulphasalazine (50-500 mum) suppressed nit ric oxide (NO) production in a concentration-dependent manner. The expressi on of the inducible NO synthase (iNOS) was suppressed by sulphasalazine at 500 mum. Sulphasalazine inhibited the LPS/IFN-gamma -induced production of both interleukin-12 (IL-12) p40 and p70. The suppression of both NO and IL- 12 production by sulphasalazine was superior to that by either sulphapyridi ne or 5-aminosalicylic acid. Although the combination of LPS and IFN-gamma induced a rapid expression of the active forms of p38 and p42/44 mitogen-ac tivated protein kinases and c-Jun terminal kinase, sulphasalazine failed to interfere with the activation of any of these kinases. Finally, sulphasala zine suppressed the IFN-gamma -induced expression of major histocompatibili ty complex class II. These results demonstrate that the M phi is an importa nt target of the immunosuppressive effect of sulphasalazine.