title: Hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway.
abstract: 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)-kappaB 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 IkappaB kinase signalsome and, subsequently, IkappaBalpha, leading to activation of NF-kappaB. Meanwhile, VCAM-1 production was correspondingly upregulated. Blocking NF-kappaB signaling pathway by expression of dominant-negative mutants of IkappaB kinase and IkappaBalpha suppressed HIMF-induced VCAM-1 upregulation. HIMF also strongly induced phosphorylation of Akt. A dominant-negative mutant of PI-3K, Deltap85, as well as PI-3K inhibitor, LY294002, also blocked HIMF-induced NF-kappaB 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.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University, 7th Floor, Desloge Towers, MO 63110-2539, USA.
authors.forename: Qiangsong
authors.initials: Q
authors.lastname: Tong
authors.forename: Liduan
authors.initials: L
authors.lastname: Zheng
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Danming
authors.initials: D
authors.lastname: Wang
authors.forename: Dechun
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D020871:RNA Stability; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; C413576:Retnla protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt