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

Abstract

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, confirming 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.

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