title: Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha.
abstract: We have used fas-defective MRL-lpr/lpr mice to study the effects of the staphylococcal enterotoxin superantigens on the development of autoimmune, inflammatory joint disease in animals that are susceptible to the development of rheumatoid arthritis-like disease. We show that systematic administration by a single i.p. injection of staphylococcal enterotoxin B (SEB; 10 micrograms/mouse) caused a mild, inflammatory arthritis +30 days postchallenge in the knee joints of young (< 2-mo-old) MRL-lpr/lpr mice, but not aged-matched MRL +/+ mice. In aged (> 8-mo-old) MRL-lpr/lpr mice, but not in aged MRL +/+ mice, SEB caused a severe, inflammatory arthritis, as assessed histologically, and systemic autoimmune disease, including glomerulonephritis and autoantibody production. Furthermore, in aged MRL-lpr/lpr mice, SEB but not heat-denatured SEB caused acute weight loss and elevated levels of serum proinflammatory cytokines. Compared with highly purified peritoneal macrophages obtained from either aged MRL +/+, young MRL-lpr/lpr, or young MRL +/+, peritoneal macrophages obtained from aged MRL-lpr/lpr mice constitutively expressed 2- to 10-fold greater levels of TNF-alpha, IL-1 beta, IL-6, and IL-10, and produced elevated amounts of these cytokines when treated in vitro with SEB. SEB-challenged aged MRL-lpr/lpr mice treated with anti-TNF mAb (100 micrograms/mouse; every other day), anti-V beta 8 TCR mAb (250 micrograms/mouse; every other day), or orally with the novel TNF-alpha inhibitor MDL 201,449A (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine; 25 mg/kg/day) exhibited reduced inflammatory arthritis, autoantibody formation, and serum TNF-alpha levels, but not IL-10 levels, after +30 days of treatment. These data suggest that SEB is an extremely potent macrophage-activating factor in vitro and in vivo, enhancing several aspects of autoimmune disease in MRL-lpr/lpr mice, and that anti-TNF therapies may have potential use in inflammatory arthritis.
authors: Department of Immunology, Hoechst Marion Roussel, Cincinnati, OH 45215, USA.
authors: C K
authors: CK
authors: Edwards
authors: T
authors: T
authors: Zhou
authors: J
authors: J
authors: Zhang
authors: T J
authors: TJ
authors: Baker
authors: M
authors: M
authors: De
authors: R E
authors: RE
authors: Long
authors: D R
authors: DR
authors: Borcherding
authors: T L
authors: TL
authors: Bowlin
authors: H
authors: H
authors: Bluethmann
authors: J D
authors: JD
authors: Mountz
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology*; D001170:Arthritis, Infectious / Q000276:immunology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000150:complications / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004768:Enterotoxins / Q000276:immunology*; D005921:Glomerulonephritis / Q000150:complications / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011489:Protein Denaturation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000502:physiology; D018089:Superantigens / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D016207:Cytokines; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C031818:enterotoxin B, staphylococcal