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Sci. Signal., 26 June 2012
Vol. 5, Issue 230, p. ec174
[DOI: 10.1126/scisignal.2003338]

EDITORS' CHOICE

Immunology RIGing the Antibacterial Response

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Signaling by Toll-like receptors (TLRs), which detect microbial products at the plasma membrane and endosomal compartments, activates the transcription factors nuclear factor {kappa}B (NF-{kappa}B) and interferon regulatory factor 5 (IRF5). NF-{kappa}B activates expression of several genes encoding proinflammatory cytokines that help to clear infection. IRF5 induces expression of the gene encoding the p40 subunit of the cytokine interleukin-12 (IL-12p40), which is a constituent of the heterodimeric cytokines IL-12 and IL-23. IL-12 and IL-23 stimulate the differentiation of T cells into T helper 1 (TH1) and TH17 cells, which help to clear bacteria. RIG-I–like receptor (RLR) family members are cytosolic sensors of double-stranded RNA (dsRNA) produced by viral replication, and they activate the transcription factor IRF3 to induce expression of genes encoding type I interferons (IFNs) as part of the antiviral response (see commentary by Takeuchi). Negishi et al. found that stimulation of mouse macrophages with RLR ligands blocked subsequent TLR-induced expression of Il12b, which encodes IL-12p40, and that this effect was independent of type I IFNs. RLR stimulation resulted in the recruitment of IRF3 to the Il12b promoter, where it suppressed expression by preventing the formation of a productive transcription complex. TLR-dependent recruitment of IRF5 to the Il12b promoter after previous RLR stimulation occurred only in IRF3-deficient cells. Infection of mice with Listeria monocytogenes resulted in the production of TH1 and TH17 cells, whereas coinfection with vesicular stomatitis virus (VSV) inhibited TH1 and TH17 cell production in an IRF3-dependent manner. Coinfected mice had more bacteria than did mice infected with L. monocytogenes alone, and virally infected cells died in response to doses of bacteria that are normally sublethal. Together, these data suggest that activation of IRF3 through the antiviral response suppresses TLR-induced production of IL-12 and IL-23 to inhibit antibacterial responses.

H. Negishi, H. Yanai, A. Nakajima, R. Koshiba, K. Atarashi, A. Matsuda, K. Matsuki, S. Miki, T. Doi, A. Aderem, J. Nishio, S. T. Smale, K. Honda, T. Taniguchi, Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat. Immunol. 13, 659–666 (2012). [PubMed]

O. Takeuchi, IRF3: A molecular switch in pathogen responses. Nat. Immunol. 13, 634–635 (2012). [PubMed]

Citation: J. F. Foley, RIGing the Antibacterial Response. Sci. Signal. 5, ec174 (2012).



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