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

Joseph E. Qualls, Geoffrey Neale, Amber Smith, Mi Sun Koo, Ashley A. DeFreitas, Huiyuan Zhang, Gilla Kaplan, Stephanie S. Watowich, Peter J. Murray

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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 expression of Arg1 during intracellular infections, whereas another pathway, which depends on signal transducer and activator of transcription 6 (STAT6), is required for Arg1 expression in alternatively activated macrophages. We found that mycobacteria-infected macrophages produced soluble factors, including interleukin-6 (IL-6), IL-10, and granulocyte colony-stimulating factor (G-CSF), that induced expression of Arg1 in an autocrine-paracrine manner. Arg1 expression was controlled by the MyD88-dependent production of these cytokines rather than by cell-intrinsic MyD88 signaling to Arg1. Our study revealed that the MyD88-dependent pathway that induced the expression of Arg1 after infection by mycobacteria required STAT3 activation and that this pathway may cause the development of an immunosuppressive niche in granulomas because of the induced production of Arg1 in surrounding uninfected macrophages.

Original languageEnglish (US)
JournalScience Signaling
Volume3
Issue number135
DOIs
StatePublished - Aug 17 2010

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Paracrine Communication
Arginase
Macrophages
Mycobacterium
Arginine
Cytokines
Differentiation Antigens
Nitric Oxide
STAT6 Transcription Factor
Signal transduction
Mycobacterium Infections
Poisons
Toll-Like Receptors
Pathogens
Granulocyte Colony-Stimulating Factor
Myeloid Cells
Immunosuppressive Agents
Cytotoxicity
Granuloma
Nitric Oxide Synthase

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. / Qualls, Joseph E.; Neale, Geoffrey; Smith, Amber; Koo, Mi Sun; DeFreitas, Ashley A.; Zhang, Huiyuan; Kaplan, Gilla; Watowich, Stephanie S.; Murray, Peter J.

In: Science Signaling, Vol. 3, No. 135, 17.08.2010.

Research output: Contribution to journalArticle

Qualls, JE, Neale, G, Smith, A, Koo, MS, DeFreitas, AA, Zhang, H, Kaplan, G, Watowich, SS & Murray, PJ 2010, 'Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling', Science Signaling, vol. 3, no. 135. https://doi.org/10.1126/scisignal.2000955
Qualls, Joseph E. ; Neale, Geoffrey ; Smith, Amber ; Koo, Mi Sun ; DeFreitas, Ashley A. ; Zhang, Huiyuan ; Kaplan, Gilla ; Watowich, Stephanie S. ; Murray, Peter J. / Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. In: Science Signaling. 2010 ; Vol. 3, No. 135.
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