title: Liver X receptor and STAT1 cooperate downstream of Gas6/Mer to induce anti-inflammatory arginase 2 expression in macrophages.
abstract: Mer signaling increases the transcriptional activity of liver X receptor (LXR) to promote the resolution of acute sterile inflammation. Here, we aimed to understand the pathway downstream of Mer signaling after growth arrest-specific protein 6 (Gas6) treatment that leads to LXR expression and transcriptional activity in mouse bone-marrow derived macrophages (BMDM). Gas6-induced increases in LXRα and LXRβ and expression of their target genes were inhibited in BMDM from STAT1(-/-) mice or by the STAT1-specific inhibitor fludarabine. Gas6-induced STAT1 phosphorylation, LXR activation, and LXR target gene expression were inhibited in BMDM from Mer(-/-) mice or by inhibition of PI3K or Akt. Gas6-induced Akt phosphorylation was inhibited in BMDM from STAT1(-/-) mice or in the presence of fludarabine. Gas6-induced LXR activity was enhanced through an interaction between LXRα and STAT1 on the DNA promoter of Arg2. Additionally, we found that Gas6 inhibited lipopolysaccharide (LPS)-induced nitrite production in a STAT1 and LXR pathway-dependent manner in BMDM. Additionally, Mer-neutralizing antibody reduced LXR and Arg2 expression in lung tissue and enhanced NO production in bronchoalveolar lavage fluid in LPS-induced acute lung injury. Our data suggest the possibility that the Gas6-Mer-PI3K/Akt-STAT1-LXR-Arg2 pathway plays an essential role for resolving inflammatory response in acute lung injury.
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Si-Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Lim
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Young-So
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Department of Pharmacology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.affiliation: Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000071518:Liver X Receptors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001119:Arginase; D036341:Intercellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D019869:Phosphatidylinositol 3-Kinases; D050794:STAT1 Transcription Factor; D000099255:Growth Arrest-Specific Protein 6; C494080:Stat1 protein, mouse; C481673:Arg2 protein, mouse