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Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13487-91. doi: 10.1073/pnas.1312525110. Epub 2013 Jul 29.

Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling.

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  • 1Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.

Abstract

The anti-inflammatory drug high-dose intravenous immunoglobulin, widely used to suppress inflammation, depends on a specific α-2,6-sialylated glycoform of IgG Fc to induce Interleukin 4 (IL-4) and Signal Transducer and Activator of Transcription 6 (STAT6) signaling for its activity. Here we show that anti-inflammatory activities of IL-4 can be attributed to the direct action of this cytokine on myeloid effector cells, depending on their expression of the IL-4 receptor alpha chain (IL-4Rα/CD124). However, in their basal state, these cells express low levels of IL-4Rα and would not be expected to result in significant signaling compared with other cell populations. This apparent paradox can be explained by the observation that during inflammation, triggered by a variety of stimuli (including autoantibodies, adjuvants, and TLR ligands), IL-4Rα is up-regulated specifically on these cells, priming them for STAT6 signaling. The regulation is mediated by a soluble, proteinase K-sensitive factor, released to the circulation by bone marrow-derived, non-B/non-T cells found in several organs, including the lungs, and fat. We propose that this regulation is part of a homeostatic mechanism to limit excessive inflammation and tissue damage. High-dose intravenous immunoglobulin thus exploits an endogenous feedback loop, general to inflammation, that could be further targeted for therapeutic purposes.

KEYWORDS:

macrophages; monocytes; neutrophils

PMID:
23898202
[PubMed - indexed for MEDLINE]
PMCID:
PMC3746917
Free PMC Article
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