Exogenous and endogenous catecholamines inhibit the production of macrophage inflammatory protein (MIP) 1α via a β adrenoceptor mediated mechanism

1. Noradrenaline (NA) and adrenaline (Ad) are modulators of cytokine production. Here we investigated the role of these neurotransmitters in the regulation of macrophage inflammatory protein (MIP)-1α expression. 2. Pretreatment of RAW 264.7 macrophages with NA or Ad decreased, in a concentration-dependent manner (1 nM-100 μM), MIP-1α release induced by bacterial lipopolysaccharide (LPS 10 ng ml^-1 LPS). The effect of NA was reversed by the selective β-adrenoceptor antagonist propranolol (10 μM), but not by the α-adrenoceptor antagonist phentolamine (10 μM). 3. In the concentration range of 10 nM-10 μM, isoproterenol, a β-adrenoceptor agonist, but not phenylephrine (a selective α₁-adrenoceptor agonist) or UK-14304 (a selective α₂-adrenoceptor agonist) mimicked the inhibitory effects of catecholamines on MIP-1α production. Increases in intracellular cyclic adenosine monophosphate, elicited either by the selective type IV phosphodiesterase inhibitor rolipram (0.1-10 μM), or by prostaglandin E₂, (10 nM-10 μM) decreased MIP-1α release, suggesting that increased cyclic AMP may contribute to the suppression of MIP-1α release by β-adrenoceptor stimulation. 4. Northern blot analysis demonstrated that NA (100 nM-10 μM), Ad, isoproterenol, as well as rolipram (100 nM-10 μM) decreased LPS-induced MIP-1α mRNA accumulation. NA and Ad (1-100 μM) also decreased MIP-1α production in thioglycollate-elicited murine peritoneal macrophages. 5. Pretreatment of mice with either isoproterenol (10 mg kg^-1, i.p.) or rolipram (25 mg kg^-1, i.p.) decreased LPS-induced plasma levels of MIP-1α, while propranolol (10 mg kg^-1, i.p.) augmented the production of this chemokine, confiming the role of a β-adrenoceptor mediated endogenous catecholamine action in the regulation of MIP-1α production in vivo. 6. Thus, based on our data we conclude that catecholamines are important endogenous regulators of MIP-1α expression in inflammation.