Melatonin has been shown to be produced by nonpineal cells and possess anti-inflammatory actions in animal models. In the present study, we tested the hypothesis that melatonin suppresses the expression of proinflammatory genes such as cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (INOS) by a common transcriptional mechanism. Melatonin but not tryptophan or serotonin inhibited lipopolysaccharide (LPS)-induced COX-2 and iNOS protein levels and promoter activities in RAW 264.7 cells in a time-and concentration-dependent manner. LPS or LPS plus interferon-␥ (IFN␥) increased binding of all 5 isoforms of NF-B to COX-2 and iNOS promoters. Melatonin selectively inhibited p52 binding without affecting p100 expression, p52 generation from p100, or p52 nuclear translocation. p52 acetylation was enhanced by LPS, which was abrogated by melatonin. Melatonin inhibited p300 histone acetyltransferase (HAT) activity and abrogated p300-augmented COX-2 and iNOS expression. HAT inhibitors suppressed LPS-induced p52 binding and acetylation to an extent similar to melatonin, and melatonin did not potentiate the effect of HAT inhibitors. These results suggest that melatonin inhibits COX-2 and iNOS transcriptional activation by inhibiting p300 HAT activity, thereby suppressing p52 acetylation, binding, and transactivation. ( IntroductionMelatonin is produced primarily in the pineal gland and secreted into circulating blood. It has been shown that melatonin is also produced by cells including monocytes and macrophages and has been implicated in protection against inflammation (for a review, see Reiter 1 ). Depletion of endogenous melatonin has been shown in rats to aggravate carrageenan-induced pleurisy, which is reversed by exogenous melatonin, 2 while exogenous melatonin administration has been demonstrated to reduce acute inflammatory reactions in zymosan-activated plasma-induced paw inflammation 3 and carrageenan-induced edema and pleurisy. 4 Its anti-inflammatory actions are attributed to its ability to scavenge reactive oxygen species and suppress proinflammatory genes, including inducible nitric oxide synthase (INOS) and cyclooxygenase-2 (COX2). 5,6 iNOS (also known as NOS-2) and COX-2 play an important role in diverse inflammatory conditions including vascular inflammation, atherosclerosis, and plaque stability. 7-10 iNOS catalyzes the robust synthesis of nitric oxide (NO) from L-arginine. 11 NO induces inflammatory reactions and tissue injury by diverse mechanisms including activation of soluble guanylyl cyclase, protein nitration, and nitrosylation. 12-14 COX-2 occupies a key position in production of proinflammatory prostanoids such as prostaglandin E 2 (PGE 2 ). 15 iNOS and COX-2 share similar cellular and molecular properties. 16 Their expressions are highly inducible by cytokines and lipopolysaccharide (LPS). [17][18][19][20] They are coinduced in inflammatory cells and their products work in concert to cause tissue inflammation and damage. 7 Transcriptional regulation of COX2 and INOS in murine RAW 264.7 ce...
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