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J. Biol. Chem., Vol. 281, Issue 50, 38712-38720, December 15, 2006

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Monocyte Differentiation, Activation, and Mycobacterial Killing Are Linked to Transsulfuration-dependent Redox Metabolism^*

Sanjay Garg, Victor Vitvitsky, Howard E. Gendelman^¶, and Ruma Banerjee¹

From the Redox Biology Center and the Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588-0664 and the Department of Pharmacology and Experimental Neuroscience, ^¶Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880

Modulation of the ambient redox status by mononuclear phagocytes is central to their role in health and disease. However, little is known about the mechanism of redox regulation during mononuclear phagocyte differentiation and activation, critical cellular steps in innate immunity, and microbial clearance. An important intermediate in GSH-based redox metabolism is homocysteine, which can undergo transmethylation via methionine synthase (MS) or transsulfuration via cystathionine -synthase (CBS). The transsulfuration pathway generates cysteine, the limiting reagent in GSH biosynthesis. We now demonstrate that expression of CBS and MS are strongly induced during differentiation of human monocytes and are regulated at the transcriptional and posttranscriptional levels, respectively. The changes in enzyme expression are paralleled by an 150% increase in S-adenosylmethionine (accompanied by a corresponding increase in phospholipid methylation) and a similar increase in GSH. Activation with lipopolysachharide or infection with Mycobacterium smegmatis diminished expression of both enzymes to a significant extent and decreased S-adenosylmethionine concentration by 30% of the control value while GSH and cysteine concentrations increased 100 and 300%, respectively. Blockade of the transsulfuration pathway with propargylglycine suppressed clearance of M. smegmatis by macrophages and inhibited phagolysosomal fusion, whereas N-acetylcysteine promoted phagolysosomal fusion and enhanced mycobacterial clearance 3-fold compared with untreated cells. We posit that regulation of the transsulfuration pathway during monocyte differentiation, activation, and infection can boost host defense against invading pathogens and may represent a heretofore unrecognized antimicrobial therapeutic target.

Received for publication, June 29, 2006 , and in revised form, October 2, 2006.

^* This work was supported by National Institutes of Health Grants DK64959 (to R. B.) and 5 R37 NS36126-07, 5 R01 NS034239-10, 1 P01 NS43985-01A1, and 20 RR15635 (to H. E. G.) and from the Jonty Foundation (to R. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 402-472-2941; Fax: 402-472-4961; E-mail: rbanerjee1{at}unl.edu.

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