title: Activation of Jun N-terminal kinase/stress-activated protein kinase pathway by tumor necrosis factor alpha leads to intercellular adhesion molecule-1 expression.
abstract: Tumor necrosis factor alpha (TNF-alpha) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. We have previously shown that mouse Sertoli cells respond to TNF-alpha by increasing interleukin-6 production and intercellular adhesion molecule-1 (ICAM-1) expression (1). In this cell type TNF-alpha activates the mitogen-activated protein kinase (MAPK) pathways p42/p44 MAPK, JNK/SAPK, and p38, the last of which is responsible for interleukin-6 production (1). To determine which MAPK signaling pathway is required for TNF-alpha induction of ICAM-1 expression, we have utilized the protein kinase inhibitor dimethylaminopurine, demonstrating that treatment of Sertoli cells with such compound significantly reduced ICAM-1 expression and JNK/SAPK activation. Moreover, dimethylaminopurine treatment increased the expression of MAPK phosphatase-2, providing a possible mechanism of action of this compound. By using agonist antibodies to p55 and to p75 TNF-alpha receptors and both human and mouse TNF-alpha, we demonstrate that both TNF receptors are expressed and that only the p55 receptor is involved in ICAM-1 expression. The p55 receptor activates all of the three pathways, whereas p75 failed to activate any of the MAPKs. Altogether our results demonstrate that TNF-alpha up-regulates ICAM-1 expression through the activation of the JNK/SAPK transduction pathway mediated by the p55 receptor.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Histology University of Rome "La Sapienza," 00161 Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: De Cesaris
authors.forename: D
authors.initials: D
authors.lastname: Starace
authors.forename: G
authors.initials: G
authors.lastname: Starace
authors.forename: A
authors.initials: A
authors.lastname: Filippini
authors.forename: M
authors.initials: M
authors.lastname: Stefanini
authors.forename: E
authors.initials: E
authors.lastname: Ziparo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D054637:Dual-Specificity Phosphatases; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D012708:Sertoli Cells; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C001020:N(6),N(6)-dimethyladenine; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054648:Protein Phosphatase 2; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases; D000225:Adenine