title: Infliximab neutralizes the suppressive effect of TNF-alpha on expression of extracellular-superoxide dismutase in vitro.
abstract: Extracellular-superoxide dismutase (EC-SOD) is the major SOD isozyme in blood vessel walls, normal cartilage and synovial fluid and may be important for the antioxidant capability of these tissues. We have reported that EC-SOD gene transferred mice exhibited significant suppression of clinical symptoms of type II collagen induced arthritis [Iyama, et al., Arthritis Rheum., 44, 2160-2167 (2001)] and plasma EC-SOD levels in type 2 diabetic patients were significantly negatively related to indices of insulin resistance [Adachi, et al., J. Endocrinol., 181, 413-417 (2004)]. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathological conditions of the above diseases and is a major therapeutic target, based on clinical studies with anti-TNF-alpha monoclonal antibodies such as infliximab. In this report, we investigated the effect of TNF-alpha on the expression of EC-SOD in cultured cells and the cooperating effect of infliximab. In the in vitro assays examined, expression of EC-SOD, but not other SOD isozymes, in smooth muscle and fibroblast cells were suppressed by the addition of TNF-alpha. Simultaneous addition of infliximab dose-dependently and significantly prevented the suppressive effects of TNF-alpha. p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, prevented significantly the suppressive effect of TNF-alpha suggesting that p38 MAPK is an important signaling molecule downstream of TNF-alpha to inhibit the EC-SOD expression. From the results, it is speculated that the decline in TNF-alpha activity by the administration of infliximab results in the liberation of EC-SOD from the suppressed state of gene expression. This reveals a potential usefulness of infliximab on TNF-alpha related pathological conditions such as arthritis and insulin resistance.
authors.affiliation: Department of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan. adachi@gifu-pu.ac.jp
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Adachi
authors.forename: Taisuke
authors.initials: T
authors.lastname: Toishi
authors.forename: Eiji
authors.initials: E
authors.lastname: Takashima
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hara
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D000069285:Infliximab; D012333:RNA, Messenger / Q000032:analysis; D013482:Superoxide Dismutase / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases