MDP(LYSYL)GDP, A NONTOXIC MURAMYL DIPEPTIDE DERIVATIVE, INHIBITS CYTOKINE PRODUCTION BY ACTIVATED MACROPHAGES AND PROTECTS MICE FROM PHORBOL ESTER-INDUCED AND OXAZOLONE-INDUCED INFLAMMATION

High levels of pro-inflammatory cytokines and nitric oxide are propose d to orchestrate pathophysiologic mechanism(s) associated with various inflammatory dermatoses. This study examines whether a water soluble 3-O-[N- acetylmuramyl-L-lysyl-D-iso]-2-di-on-glycine [MDP(Lysyl)GDP], a nontoxic and nonpyrogenic derivative of muramyl dipeptide (MDP), can inhibit the in vitro production of inflammatory mediators by lipopoly saccharide- or interferon-gamma-activated macrophages, and whether suc h an inhibitory effect can translate into in vivo protection of mice f rom irritant and allergic contact dermatitis. Thioglycollate-elicited peritoneal macrophages cultured in medium alone or in medium supplemen ted with MDP(Lysyl)GDP (1-100 mu g per mi) expressed neither mRNA tran scripts for inducible nitric oxide synthase, interleukin-1 beta, and t umor necrosis factor-alpha, nor cytokine proteins and nitric oxide act ivity. Incubation of the cells with either lipopolysaccharide or inter feron-gamma for 6 h resulted in a significant induction of inducible n itric oxide synthase, interleukin-1 beta, and tumor necrosis factor-al pha mRNA, and the accumulation of high levels of monokines and nitrite s in cultures by 24 h, Coincubation of the macrophages with lipopolysa ccharide or interferon-gamma and MDP(Lysyl)GDP (1-100 mu g per mi) res ulted in a concentration-dependent suppression of the steady-state mRN A transcripts for inducible nitric oxide synthase, tumor necrosis fact or-alpha, and interleukin-1 beta, induced by lipopolysaccharide, but n ot by interferon-gamma, In mouse models of phorbol ester- and oxazolon e-induced ear inflammation, topical application of MDP(Lysyl)GDP signi ficantly suppressed ear swelling in a dose-dependent manner. Likewise, oral treatment with MDP(Lysyl)GDP at days -3, -2, and -1 before elici tation with oxazolone also significantly inhibited ear inflammation, T aken together, our findings suggest that MDP(Lysyl)GDP has the potenti al to be a therapeutic application in the treatment of inflammatory co nditions in which overproduction of pro-inflammatory mediators are imp licated to play a pathogenic role.