EXOGENOUS AND ENDOGENOUS CATECHOLAMINES INHIBIT THE PRODUCTION OF MACROPHAGE INFLAMMATORY PROTEIN (MIP) 1-ALPHA VIA A BETA-ADRENOCEPTOR-MEDIATED MECHANISM

1 Noradrenaline (NA) and adrenaline (Ad) are modulators of cytokine pr oduction. Here we investigated the role of these neurotransmitters in the regulation of macrophage inflammatory protein (MIP)-1 alpha expres sion. 2 Pretreatment of RAW 264.7 macrophages with NA or Ad decreased, in a concentration-dependent manner (1 nM-100 mu M), MIP-1 alpha rele ase induced by bacterial lipopolysaccharide (LPS 10 ng ml(-1) LPS). Th e effect of NA was reversed by the selective beta-adrenoceptor antagon ist propranolol. (10 mu M), but not by the alpha-adrenoceptor antagoni st phentolamine (10 mu M). 3 In the concentration range of 10 nM-10 mu M, isoproterenol, a beta-adrenoceptor agonist, but not phenylephrine (a selective alpha(1)-adrenoceptor agonist) or UK-14304 (a selective a lpha(2)-adrenoceptor agonist) mimicked the inhibitory effects of catec holamines on MIP-1 alpha production. Increases in intracellular cyclic adenosine monophosphate, elicited either by the selective type IV pho sphodiesterase inhibitor rolipram (0.1-10 mu M), or by prostaglandin E -2, (10 nM-10 mu M) decreased MIP-1 alpha release, suggesting that inc reased cyclic AMP may contribute to the suppression of MIP-1 alpha rel ease by beta-adrenoceptor stimulation. 4 Northern blot analysis demons trated that NA (100 nM-10 mu M), Ad, isoproterenol, as well as rolipra m (100 nM-10 mu M) decreased LPS-induced MIP-1 alpha mRNA accumulation . NA and Ad (1-100 mu M) also decreased MIP-1 alpha production in thio glycollate-elicited murine peritoneal macrophages. 5 Pretreatment of m ice with either isoproterenol (10 mg kg(-1), i.p.) or rolipram (25 mg kg(-1), i.p.) decreased LPS-induced plasma levels of MIP-1 alpha, whil e propranolol (10 mg kg(-1), i.p.) augmented the production of this ch emokine, confirming the role of a beta-adrenoceptor mediated endogenou s catecholamine action in the regulation of MIP-1 alpha production in vivo. 6 Thus, based on our data we conclude that catecholamines are im portant endogenous regulators of MIP-1 alpha expression in inflammatio n.