title: Pulmonary surfactant protein A and surfactant lipids upregulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages.
abstract: 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.
authors.affiliation: Dept. of Microbial Infection and Immunity, The Ohio State Univ., Columbus, OH 43210, USA.
authors.forename: Huy A
authors.initials: HA
authors.lastname: Nguyen
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Meyer
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D037662:Pulmonary Surfactant-Associated Protein A; D011663:Pulmonary Surfactants; D051193:Toll-Like Receptors; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases