title: Tumor necrosis factor receptor (TNFR) 1, but not TNFR2, mediates tumor necrosis factor-alpha-induced interleukin-6 and RANTES in human airway smooth muscle cells: role of p38 and p42/44 mitogen-activated protein kinases.
abstract: Little information is available regarding the mechanisms involved in cytokine-induced synthetic function of human airway smooth muscle (ASM) cells. Here, we report that tumor necrosis factor receptor (TNFR) 1-induced p38 and p42/44 mitogen-activated protein kinase (MAPK) activation modulates tumor necrosis factor-alpha (TNF alpha)-mediated synthetic responses: expression of intercellular adhesion molecule-1 (ICAM-1) and secretion of interleukin (IL)-6 and the regulated-on-activation, normal T-cell expressed and secreted (RANTES) chemokine in human ASM cells. Pretreatment of ASM cells with SB203580, a p38 MAPK inhibitor, slightly enhanced TNF alpha-induced ICAM-1 expression in a dose-dependent manner but partially inhibited secretion of RANTES and IL-6. In contrast, PD98059, a p42/44 inhibitor, reduced ICAM-1 expression by 50% but had no effect on TNF alpha-induced RANTES or IL-6 secretion. SB203580 and PD98059 had little effect on TNF alpha-induced nuclear factor-kappa B (NF-kappa B) activation as determined in cells transfected with a NF-kappa B-luciferase reporter construct. We also found that agonistic antibodies specific for either TNFR1 or TNFR2 stimulated IL-6 and RANTES secretion and activated p38 and p42/44 MAPKs. In addition, both antibodies induced NF-kappa B-mediated gene transcription. Using receptor-specific blocking antibodies, we found that TNFR1 primarily regulates TNF alpha-induced IL-6 and RANTES secretion and activation of p38 and p42/44 MAPK pathways. Interestingly, we found that TNFR1 and TNFR2 are expressed differently on the cell surface of ASM cells. Our data suggest that despite the presence of functional TNFR2, TNFR1 associated with MAPK-dependent and -independent pathways is the primary signaling pathway involved in TNF alpha-induced synthetic functions in ASM cells.
authors.affiliation: Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6160, USA. amrani@mail.med.upenn.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Amrani
authors.forename: A J
authors.initials: AJ
authors.lastname: Ammit
authors.forename: R A
authors.initials: RA
authors.lastname: Panettieri
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000201:enzymology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009130:Muscle, Smooth / Q000201:enzymology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015703:Antigens, CD; D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one