INVOLVEMENT OF ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA AND TRANSFORMING GROWTH-FACTOR-BETA DURING INDUCTION OF COLLAGEN TYPE-II ARTHRITIS IN MICE

Both tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) are found in synovial fluid from arthritic joints of humans and of rodents with experimental arthritis. The role of endogenously produced TGF-beta and TNF in the pathogenesis of collagen type II-induced arthritis (CIA) in DBA/1 mice was examined by determining the effect of neutralizing monoclonal antibodies to these factors on the course of the disease. Endogenously produced as well as systemically administered TGF-beta-1 and TNF-alpha had opposite effects, since TGF-beta-1 and anti-TNF protected against CIA, whereas anti-TGF-beta and TNF-alpha increased CIA incidence and/or severity. Intraperitoneally injected TGF-beta-1 at a dose of 2-mu-g per day for 14 days significantly ameliorated arthritis, even when started at the time of arthritis development, although it did not reverse established disease. The resistance to CIA induction caused by a prior intravenous injection of collagen type II was not significantly influenced by the simultaneous injection of TGF-beta-1, TNF-alpha, or interleukin 1-alpha. It is concluded that the endogenous production of TNF and TGF-beta is important in determining the course of CIA.