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Signal Transduction Mechanisms of IL‐8‐Induced Endothelial Permeability
Author(s) -
Petreaca M.L.,
Yao M.,
MartinsGreen M.
Publication year - 2008
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1067-1927.2005.130215bh.x
Subject(s) - rhoa , microbiology and biotechnology , signal transduction , pertussis toxin , endothelial stem cell , chemistry , angiogenesis , vascular permeability , receptor , g protein , biology , biochemistry , endocrinology , cancer research , in vitro
Permeability of the endothelium occurs early in the angiogenic process, resulting from the initial loss or disruption of endothelial cell‐cell adhesions, which is followed by endothelial cell contraction, forming paracellular gaps. We are interested in the angiogenesis and endothelial permeability induced by inflammation; thus, we have chosen to study mechanisms involved in the endothelial permeability stimulated by the angiogenic chemokine Interleukin‐8 (IL‐8/CXCL8). We have found that IL‐8 induces permeability in a receptor‐dependent process requiring the activation of G αi and the regulation of PKA activity. Pertussis toxin abolishes the effect of IL‐8 on endothelial permeability, while a PKA inhibitor, H89, results in a similar effect. Thus, regulation of the level of PKA activity appears critical in IL‐8‐induced permeability, potentially due to the differential regulation of molecules downstream of PKA, such as SREBP and RhoA. PKA and cAMP are thought to inhibit the activation of SREBP, a protein involved in lipid metabolism; we have also found, using inhibitors of SREBP that this molecule is likewise necessary for the permeability stimulated by IL‐8. Furthermore, SREBP inhibitors block IL‐8‐induced activation of RhoA, a GTPase that has been implicated in permeability induced by multiple factors. Taken together, our results indicate a possible signal transduction pathway downstream of the IL‐8 receptors, in which the inhibition of cAMP production, and, thus, of PKA activation, by G αi increases SREBP activity, resulting in increased RhoA activity, leading to endothelial cell contraction and gap formation, increasing endothelial permeability. Because IL‐8 plays important roles in the permeability observed in inflammatory disorders, knowledge of the signaling mechanisms induced by this chemokine during permeability increases may be used to identify targets for drug development. This project has been funded by the American Heart Association.