title: Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF-κB activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury.
abstract: Mer signaling participates in a novel inhibitory pathway in TLR activation. The purpose of the present study was to examine the role of Mer signaling in the down-regulation of TLR4 activation-driven immune responses in mice, i.t.-treated with LPS, using the specific Mer-blocking antibody. At 4 h and 24 h after LPS treatment, expression of Mer protein in alveolar macrophages and lung tissue decreased, sMer in BALF increased significantly, and Mer activation increased. Pretreatment with anti-Mer antibody did not influence the protein levels of Mer and sMer levels. Anti-Mer antibody significantly reduced LPS-induced Mer activation, phosphorylation of Akt and FAK, STAT1 activation, and expression of SOCS1 and -3. Anti-Mer antibody enhanced LPS-induced inflammatory responses, including activation of the NF-κB pathway; the production of TNF-α, IL-1β, and MIP-2 and MMP-9 activity; and accumulation of inflammatory cells and the total protein levels in BALF. These results indicate that Mer plays as an intrinsic feedback inhibitor of the TLR4- and inflammatory mediator-driven immune responses during acute lung injury.
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea. jihee@ewha.ac.kr
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Lee
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Han
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Byun
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Park
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Cho
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D000076202:c-Mer Tyrosine Kinase
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse