title: TNFα induces inflammatory stress response in microvascular endothelial cells via Akt- and P38 MAP kinase-mediated thrombospondin-1 expression.
abstract: Tumor necrosis factor-α (TNFα) and thrombospondin-1 (TSP-1) are well-known mediators of inflammation. However, a causal relationship between TNFα stimuli and TSP-1 expression in endothelial cell stress, and the underlying mechanisms has not yet been investigated. In our study, human microvascular endothelial cells (hMEC) were treated with TNFα and analyzed for endothelial dysfunction, TSP-1 expression, and associated mechanisms. TNFα treatment induced a dose-dependent increase in TSP-1 expression in hMEC associated with increased endothelial permeability, apoptosis, and reduced proliferation. Whereas TNFα activated Akt, ERK, and P38 mitogen-activated protein kinase (P38 MAPK) simultaneously in hMEC, inhibitors of Akt and P38 MAPK, but not ERK blunted TNFα-induced TSP-1 expression. Silencing of NFκB gene had no significant effect on TNFα-induced TSP-1 expression. Our study demonstrates the novel role of TNFα in inducing inflammatory stress response in hMEC through Akt- and P38 MAPK-mediated expression of TSP-1, independent of NFκB signaling.
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, HM1200, Augusta, GA, 30912, USA.
authors.forename: Arwa
authors.initials: A
authors.lastname: Fairaq
authors.forename: Anna
authors.initials: A
authors.lastname: Goc
authors.forename: Sandeep
authors.initials: S
authors.lastname: Artham
authors.forename: Harika
authors.initials: H
authors.lastname: Sabbineni
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D017209:Apoptosis; D002199:Capillary Permeability; D049109:Cell Proliferation; D002470:Cell Survival; D042783:Endothelial Cells; D004730:Endothelium, Vascular; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D055806:Microvessels; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013312:Stress, Physiological / Q000276:immunology; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C439524:TNF protein, human; D019700:Thrombospondin 1; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases