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Arginine utilization following mycobacteria infection in macrophages is dependent on autocrine-paracrine signaling

ABSTRACT: Nitric oxide (NO) produced by macrophages (MØs) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. MØ arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in MØs. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated MØs. We found that mycobacteria-infected MØs produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected MØs We used microarrays to perform genome wide expression analysis in mycobacteria-infected macrophages from C57Bl/6 WT and MyD88-knockout mice.

ORGANISM(S): Mus musculus  

SUBMITTER: Joseph E Qualls   Peter J Murray  Geoffrey Neale  Geoffrey A Neale 

PROVIDER: E-GEOD-22935 | ArrayExpress | 2010-07-14



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Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling.

Qualls Joseph E JE   Neale Geoffrey G   Smith Amber M AM   Koo Mi-Sun MS   DeFreitas Ashley A AA   Zhang Huiyuan H   Kaplan Gilla G   Watowich Stephanie S SS   Murray Peter J PJ  

Science signaling 20100817 135

Nitric oxide (NO) produced by macrophages is toxic to host tissues and invading pathogens, and its regulation is essential to suppress host cytotoxicity. Macrophage arginase 1 (Arg1) competes with NO synthases for arginine, a substrate common to both types of enzymes, to inhibit NO production. Two signal transduction pathways control the production of Arg1 in macrophages: One pathway dependent on the Toll-like receptor adaptor protein myeloid differentiation marker 88 (MyD88) induces the express  ...[more]

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