title: Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expression.
abstract: The anti-inflammatory agent sulphasalazine is an important component of several treatment regimens in the therapy of ulcerative colitis, Crohn's disease and rheumatoid arthritis. Sulphasalazine has many immunomodulatory actions, including modulation of the function of a variety of cell types, such as lymphocytes, natural killer cells, epithelial cells and mast cells. However, the effect of this agent on macrophage (M phi) function has not been characterized in detail. In the present study, we investigated the effect of sulphasalazine and two related compounds - sulphapyridine and 5-aminosalicylic acid - on M phi activation induced by bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). In J774 M phi stimulated with LPS (10 microg/ml) and IFN-gamma (100 U/ml), sulphasalazine (50-500 microM) suppressed nitric oxide (NO) production in a concentration-dependent manner. The expression of the inducible NO synthase (iNOS) was suppressed by sulphasalazine at 500 microM. 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 sulphapyridine 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-activated protein kinases and c-Jun terminal kinase, sulphasalazine failed to interfere with the activation of any of these kinases. Finally, sulphasalazine suppressed the IFN-gamma-induced expression of major histocompatibility complex class II. These results demonstrate that the M phi is an important target of the immunosuppressive effect of sulphasalazine.
authors.affiliation: Department of Surgery, UMD-New Jersey Medical School, Newark, NJ 07103, USA. haskoge@umdnj.edu
authors.forename: G
authors.initials: G
authors.lastname: Haskó
authors.forename: C
authors.initials: C
authors.lastname: Szabó
authors.forename: Z H
authors.initials: ZH
authors.lastname: Németh
authors.forename: E A
authors.initials: EA
authors.lastname: Deitch
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018929:Cell Culture Techniques; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000276:immunology; D019804:Mesalamine / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013427:Sulfapyridine / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D018664:Interleukin-12; D009569:Nitric Oxide; D012460:Sulfasalazine; D019804:Mesalamine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013427:Sulfapyridine