Infliximab Neutralizes the Suppressive Effect of TNF-α on Expression of Extracellular-Superoxide Dismutase in Vitro(Biopharmacy)

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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-α (TNF-α) has been implicated in the pathological conditions of the above diseases and is a major therapeutic target, based on clinical studies with anti-TNF-α monoclonal antibodies such as infliximab. In this report, we investigated the effect of TNF-α 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-α. Simultaneous addition of infliximab dose-dependently and significantly prevented the suppressive effects of TNF-α. p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, prevented significantly the suppressive effect of TNF-α suggesting that p38 MAPK is an important signaling molecule downstream of TNF-α to inhibit the EC-SOD expression. From the results, it is speculated that the decline in TNF-α 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-α related pathological conditions such as arthritis and insulin resistance.
公益社団法人日本薬学会の論文
2006-10-01

Infliximab Neutralizes the Suppressive Effect of TNF-α on Expression of Extracellular-Superoxide Dismutase in Vitro(Biopharmacy)

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