Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis rat

Aim: To study the effects of melatonin on inflammatory and immune responses and its mechanisms. Methods: The model of adjuvant-induced arthritis (AA) rat was induced by Freund's complete adjuvant (FCA); the thymocyte proliferation and IL-2 production were assayed by 3-(4,5-2dimethylthiazal-2yl)2,5-diphenyltetrazoliumbromide (MTT) and activated mouse splenocytes proliferation, respectively; cAMP and methionine-enkephalin (Met-Enk) level were determined by competitive protein binding assay (CPBA) and radioimmuno-assay, respectively. Results: There was a marked inflammatory response in AA model, which was accompanied by the decreases of thymocyte proliferation and IL-2 production simultaneously. The prophylactic and therapeutic administration of melatonin (1, 10 and 100 mug kg (- 1), ig x 7 days) inhibited the inflammatory response and enhanced thymocytes proliferation and IL-2 production significantly in AA rats. In vitro, melatonin, at the concentrations of 10 (- 7) and 10 (- 6) mol l (- 1) could enhance the thymocyte proliferation in AA rats, The cAMP level stimulated by forskolin (F, a selective adenylate cyclase [AC] activator) in AA rats was higher than that in the control groups. Melatonin (10 (- 10) or 10 (- 6) Mol l (- 1)) had down-regulation on the above increased cAMP levels, which could be abolished by pertussis toxin (PT). Meanwhile, the decrease of thymocyte proliferation in AA rats had a marked relation with the decrease of Met-Enk level in these thymocytes, melatonin (10 (- 10) or 10 (- 6) Mol l (- 1)) could markedly enhance the Met-Enk level, which were blocked by nifedipine, a Ca2+ channel antagonist. Conclusions: Melatonin possesses anti-inflammatory and immunoregulatory actions, the G protein-AC-cAMP transmembrane signal and Met-Enk release in thymocyte are important mechanisms of this action. (C) 2002 Elsevier Science BA. All rights reserved.