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Resistance of Macrophages to Mycobacterium avium Is Induced by ₂-Adrenergic Stimulation

Department of Microbiology, College of Biological Sciences,¹ Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210²

Received 18 April 2002/ Returned for modification 7 June 2002/ Accepted 16 September 2002

The ability of macrophages to control the growth of microorganisms is increased by macrophage activation. Previously, it was shown that epinephrine activated mouse macrophages to resist the growth of Mycobacterium avium via ₂-adrenergic stimulation. In the present study, we show that the ₂-adrenergic agonist (₂-agonist) clonidine induced resistance to M. avium growth in the RAW264.7 mouse macrophage cell line. The ability of catecholamines to induce resistance to mycobacteria was specific to ₂-adrenergic stimulation, as ₁-, ß₁-, and ß₂-agonists had no effect. Receptor signaling through Gi proteins was required. A G-protein antagonist specific for the subunits of the Go/Gi family blocked the increased resistance induced by clonidine, while a Gs-protein antagonist was without effect. Both nitric oxide (NO) production and superoxide (O₂^-) production were required for the increased resistance to M. avium growth induced by clonidine. Although NO production was required, clonidine did not increase the level of NO in M. avium-infected cells. Since NO and O₂^- interact to produce peroxynitrite (ONOO^-), we examined whether ONOO^- mediates the increased resistance to M. avium induced by clonidine. 5,10,15,20-Tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride (FeTPPS), a specific scavenger of ONOO^-, inhibited the effect of clonidine on M. avium growth. Clonidine also increased the production of ONOO^- in M. avium-infected RAW264.7 cells, as measured by the oxidation of 123-dihydrorhodamine and the production of nitrated tyrosine residues. We therefore conclude that ₂-adrenergic stimulation activates macrophages to resist the growth of M. avium by enhancing the production of ONOO^-.

Editor: W. A. Petri, Jr.

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