Document Detail

Pulmonary surfactant protein A and surfactant lipids upregulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages.
MedLine Citation:
PMID:  22886503     Owner:  NLM     Status:  MEDLINE    
Alveolar macrophages (AMs) are exposed to frequent challenges from inhaled particulates and microbes and function as a first line of defense with a highly regulated immune response because of their unique biology as prototypic alternatively activated macrophages. Lung collectins, particularly surfactant protein A (SP-A), contribute to this activation state by fine-tuning the macrophage inflammatory response. During short-term (10 min-2 h) exposure, SP-A's regulation of human macrophage responses occurs through decreased activity of kinases required for proinflammatory cytokine production. However, AMs are continuously exposed to surfactant, and the biochemical pathways underlying long-term reduction of proinflammatory cytokine activity are not known. We investigated the molecular mechanism(s) underlying SP-A- and surfactant lipid-mediated suppression of proinflammatory cytokine production in response to Toll-like receptor (TLR) 4 (TLR4) activation over longer time periods. We found that exposure of human macrophages to SP-A for 6-24 h upregulates expression of IL-1 receptor-associated kinase M (IRAK-M), a negative regulator of TLR-mediated NF-κB activation. Exposure to Survanta, a natural bovine lung extract lacking SP-A, also enhances IRAK-M expression, but at lower magnitude and for a shorter duration than SP-A. Surfactant-mediated upregulation of IRAK-M in macrophages suppresses TLR4-mediated TNF-α and IL-6 production in response to LPS, and IRAK-M knockdown by small interfering RNA reverses this suppression. In contrast to TNF-α and IL-6, the surfactant components upregulate LPS-mediated immunoregulatory IL-10 production, an effect reversed by IRAK-M knockdown. In conclusion, these data identify an important signaling regulator in human macrophages that is used by surfactant to control the long-term alveolar inflammatory response, i.e., enhanced IRAK-M activity.
Huy A Nguyen; Murugesan V S Rajaram; Douglas A Meyer; Larry S Schlesinger
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-08-10
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  303     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2013-01-04     Revised Date:  2013-10-10    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L608-16     Citation Subset:  IM    
Dept. of Microbial Infection and Immunity, The Ohio State Univ., Columbus, OH 43210, USA.
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MeSH Terms
Cells, Cultured
Cytokines / biosynthesis
Gene Knockdown Techniques
Inflammation / metabolism*
Inflammation Mediators / metabolism
Interleukin-1 Receptor-Associated Kinases / biosynthesis*,  genetics
Macrophages / metabolism*
Pulmonary Surfactant-Associated Protein A / metabolism*
Pulmonary Surfactants / metabolism*
Signal Transduction
Toll-Like Receptors / metabolism*
Grant Support
Reg. No./Substance:
0/Cytokines; 0/Inflammation Mediators; 0/Pulmonary Surfactant-Associated Protein A; 0/Pulmonary Surfactants; 0/Toll-Like Receptors; EC protein, human; EC Receptor-Associated Kinases

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