title: Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members.
abstract: Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and IL-1 stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. TNF-alpha and IL-1 regulate gene expression in ECs, in part, by stimulating mitogen-activated protein kinases (MAPK), which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAPK in EC. To test this hypothesis, we determined the effects of flow (shear stress = 12 dynes/cm(2)) on TNF-alpha and IL-1-stimulated activity of three MAPK in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), p38, and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 and p38 activity but decreased JNK activity compared with static controls. TNF-alpha or IL-1 alone activated ERK1/2, p38, and JNK maximally at 15 min in HUVEC. Preexposing HUVEC for 10 min to flow inhibited TNF-alpha and IL-1 activation of JNK by 46% and 49%, respectively, but had no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, which inhibits flow-mediated ERK1/2 activation, prevented flow from inhibiting cytokine activation of JNK. Phorbol 12-myristate 13-acetate, which strongly activates ERK1/2, also inhibited TNF-alpha activation of JNK. These findings indicate that fluid shear stress inhibits TNF-alpha-mediated signaling events in HUVEC via the activation of the ERK1/2 signaling pathway. Inhibition of TNF-alpha signal transduction represents a mechanism by which steady laminar flow may exert atheroprotective effects on the endothelium.
authors.affiliation: Department of Medicine, Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: J
authors.initials: J
authors.lastname: Surapisitchat
authors.forename: R J
authors.initials: RJ
authors.lastname: Hoefen
authors.forename: X
authors.initials: X
authors.lastname: Pi
authors.forename: M
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: C
authors.initials: C
authors.lastname: Yan
authors.forename: B C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014471:Umbilical Veins; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases