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Hypoxia-Induced Mitogenic Factor Promotes Vascular Adhesion Molecule-1 Expression via the PI-3K/Akt–NF-B Signaling Pathway

Department of Internal Medicine, Saint Louis University, St. Louis, Missouri; Department of Medicine, Johns Hopkins University, Baltimore, Maryland; and Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Correspondence and requests for reprints should be addressed to Dechun Li, M.D., Ph.D., Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University, 7th Floor, Desloge Towers, St. Louis, MO 63110-2539. E-mail: dli2{at}slu.edu

Hypoxia-induced mitogenic factor (HIMF), also known as FIZZ1 (found in inflammatory zone 1), is an important player in lung inflammation. However, the effects of HIMF on cell adhesion molecules involved in lung inflammation remain largely unknown. In the present work, we tested whether HIMF modulates vascular adhesion molecule (VCAM)-1 expression, and dissected the possible signaling pathways that link HIMF to VCAM-1 upregulation. Recombinant HIMF protein, instilled intratracheally into adult mouse lungs, results in a significant increase of VCAM-1 production in vascular endothelial, alveolar type II, and airway epithelial cells. In cultured mouse endothelial SVEC 4-10 and lung epithelial MLE-12 cells, we demonstrated that HIMF induces VCAM-1 expression via the phosphatidylinositol-3 kinase (PI-3K)/Akt–nuclear factor (NF)-B signaling pathway. Knockdown of HIMF expression by small interference RNA attenuated LPS-induced VCAM-1 expression in vitro. We showed that HIMF induced phosphorylation of the IB kinase signalsome and, subsequently, IB, leading to activation of NF-B. Meanwhile, VCAM-1 production was correspondingly upregulated. Blocking NF-B signaling pathway by expression of dominant-negative mutants of IB kinase and IB suppressed HIMF-induced VCAM-1 upregulation. HIMF also strongly induced phosphorylation of Akt. A dominant-negative mutant of PI-3K, p85, as well as PI-3K inhibitor, LY294002, also blocked HIMF-induced NF-B activation and attenuated VCAM-1 production. Furthermore, LY294002 pretreatment abolished HIMF-enhanced mononuclear cells adhesion to endothelial and epithelial cells. Our findings connect HIMF to signaling pathways that regulate inflammation, and thus reveal the critical roles that HIMF plays in lung inflammation.

Key Words: gene expression • hypoxia-induced mitogenic factor • signal transduction • vascular adhesion molecule-1

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