Integrin β4 attenuates SHP-2 and MAPK signaling and reduces human lung endothelial inflammatory responses

Weiguo Chen, Joe G.N. Garcia, Jeffrey R. Jacobson

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

We previously identified the marked upregulation of integrin β4 in human lung endothelial cells (EC) treated with simvastatin, an HMG coA-reductase inhibitor with vascular-protective and anti-inflammatory properties in murine models of acute lung injury (ALI). We now investigate the role of integrin β4 as a novel mediator of vascular inflammatory responses with a focus on mitogen-activated protein kinases (MAPK) signaling and the downstream expression of the inflammatory cytokines (IL-6 and IL-8) essential for the full elaboration of inflammatory lung injury. Silencing of integrin β4 (siITGB4) in human lung EC resulted in significant increases in both basal and LPS-induced phosphorylation of ERK 1/2, JNK, and p38 MAPK, consistent with robust integrin β4 regulation of MAPK activation. In addition, siITB4 increased both basal and LPS-induced expression of IL-6 and IL-8 mRNA and protein secretion into the media. We next observed that integrin β4 silencing increased basal and LPS-induced phosphorylation of SHP-2, a protein tyrosine phosphatase known to modulate MAPK signaling. In contrast, inhibition of SHP-2 enzymatic activity (sodium stibogluconate) abrogated the increased ERK phosphorylation associated with integrin β4 silencing in LPS-treated EC and attenuated the increases in levels of IL-6 and IL-8 in integrin-β4- silenced EC. These findings highlight a novel negative regulatory role for integrin β4 in EC inflammatory responses involving SHP-2-mediated MAPK signaling. Upregulation of integrin β4 may represent an important element of the anti-inflammatory and vascular-protective properties of statins and provides a novel strategy to limit inflammatory vascular syndromes.

Original languageEnglish (US)
Pages (from-to)718-724
Number of pages7
JournalJournal of Cellular Biochemistry
Volume110
Issue number3
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

Keywords

  • Endothelial cells
  • Inflammation
  • Integrins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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