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.