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-Mediated Innate Signal Amplification and STAT1 Phosphorylation in Resident Murine Alveolar Macrophages1
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* Pulmonary and Critical Care Medicine Section, and Research Service, Department of Veterans Affairs Medical Center, Ann Arbor, MI 48105; and
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and
Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109
The innate immune response must be mobilized promptly yet judiciously via TLRs to protect the lungs against pathogens. Stimulation of murine peritoneal macrophage (PM
) TLR4 or TLR3 by pathogen-associated molecular patterns (PAMPs) typically induces type I IFN-
, leading to autocrine activation of the transcription factor STAT1. Because it is unknown whether STAT1 plays a similar role in the lungs, we studied the response of resident alveolar macrophages (AM) or control PM from normal C57BL/6 mice to stimulation by PAMPs derived from viruses (polyriboinosinic:polyribocytidylic acid, specific for TLR3) or bacteria (Pam3Cys, specific for TLR2, and repurified LPS, specific for TLR4). AM did not activate STAT1 by tyrosine phosphorylation on Y701 following stimulation of any of these three TLRs, but readily did so in response to exogenous IFN-. This unique AM response was not due to altered TLR expression, or defective immediate-early gene response, as measured by expression of TNF-
and three chemokines. Instead, AM differed from PM in not producing bioactive IFN-, as confirmed by ELISA and by the failure of supernatants from TLR-stimulated AM to induce STAT1 phosphorylation in PM. Consequently, AM did not produce the microbicidal effector molecule NO following TLR4 or TLR3 stimulation unless exogenous IFN- was also added. Thus, murine AM respond to bacterial or viral PAMPs by producing inflammatory cytokines and chemokines, but because they lack the feed-forward amplification typically mediated by autocrine IFN- secretion and STAT1 activation, require exogenous IFN to mount a second phase of host defense.
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