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Upregulation of mer receptor tyrosine kinase signaling attenuated lipopolysaccharide-induced lung inflammations

Title
Upregulation of mer receptor tyrosine kinase signaling attenuated lipopolysaccharide-induced lung inflammations
Authors
Choi J.-Y.Park H.-J.Lee Y.-J.Byun J.Youn Y.-S.Choi J.H.Woo S.-Y.Kang J.L.
Ewha Authors
이지희우소연최지하변지연
SCOPUS Author ID
이지희scopus; 우소연scopus; 최지하scopus; 변지연scopus
Issue Date
2013
Journal Title
Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565JCR Link
Citation
vol. 344, no. 2, pp. 447 - 458
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Mer receptor tyrosine kinase (Mer) signaling plays a central role in the intrinsic inhibition of the inflammatory response to Tolllike receptor activation. Previously, we found that lung Mer protein expression decreased after lipopolysaccharide (LPS) treatment due to enhanced Mer cleavage. The purpose of the present study was to examine whether pharmacologically restored membrane-bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses. Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS-induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane-bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment. TAPI-0 also enhanced Mer downstream signaling, including phosphorylation of protein kinase b, focal adhesion kinase, and signal transducer and activator of transcription 1. As expected from enhanced Mer signaling, TAPI-0 also augmented suppressor of cytokine signaling-1 and -3 mRNA and protein levels and inhibited nuclear factor kB activation at 4 and 24 hours after LPS treatment. TAPI-0 suppressed LPS-induced inflammatory cell accumulation, total protein level elevation in BAL fluid, and production of inflammatory mediators, including tumor necrosis factor-a, interleukin-1b, and macrophage inflammatory protein-2. Additionally, the effects of TAPI-0 on the activation of Mer signaling and the production of inflammatory responses could be reversed by cotreatment with specific Merneutralizing antibody. Restored Mer protein expression by treatment with TAPI-0 efficiently prevents the inflammatory cascade during acute lung injury. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
DOI
10.1124/jpet.112.199778
Appears in Collections:
의과대학 > 의학과 > Journal papers
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