Intracellular signaling of tumor necrosis factor-alpha in brain microvascular endothelial cells is mediated by a protein tyrosine kinase and protein kinase C-dependent pathway.
The intracellular signaling pathways responsible for tumor necrosis factor (TNF)-alpha stimulation of lymphocyte adhesion to brain microvascular endothelial cells (BMEC) were studied using inhibitors of protein kinase C (bisindolylmaleimide HCl, H-7, or staurosporine), or protein tyrosine kinase (genistein). Each of these blocked the ability of BMEC to respond to TNF-alpha. In contrast, BMEC treated with H-89, an inhibitor of protein kinase A, or the adenylate cyclase inhibitor, dideoxyadenosine, responded normally to TNF-alpha. Forskolin, an adenylate cyclase agonist, significantly increased lymphocyte adhesion to BMEC. These data indicate that intracellular signaling by TNF-alpha in BMEC is mediated through a protein kinase C and tyrosine kinase dependent pathway.
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA. steve-hudson@cytelcorp.com
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D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D008214:Lymphocytes / Q000166:cytology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D004791:Enzyme Inhibitors; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C