Integrin beta4 attenuates SHP-2 and MAPK signaling and reduces human lung endothelial inflammatory responses.
We previously identified the marked upregulation of integrin beta4 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 beta4 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 beta4 (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 beta4 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 beta4 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 beta4 silencing in LPS-treated EC and attenuated the increases in levels of IL-6 and IL-8 in integrin-beta4-silenced EC. These findings highlight a novel negative regulatory role for integrin beta4 in EC inflammatory responses involving SHP-2-mediated MAPK signaling. Upregulation of integrin beta4 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.
Chen
Weiguo
W
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Garcia
Joe G N
JG
Jacobson
Jeffrey R
JR
D015153:Blotting, Western; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D039663:Integrin beta4 / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000098:blood supply; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000276:immunology / Q000378:metabolism*; D011651:Pulmonary Artery / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
D039663:Integrin beta4; D015850:Interleukin-6; D016209:Interleukin-8; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11