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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.
Mol Pharmacol. 2001 Oct; 60(4):646-55.MP

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+Show Affiliations

Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6160, USA. amrani@mail.med.upenn.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11562425

Citation

Amrani, Y, et al. "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." Molecular Pharmacology, vol. 60, no. 4, 2001, pp. 646-55.
Amrani Y, Ammit AJ, Panettieri RA. 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. Mol Pharmacol. 2001;60(4):646-55.
Amrani, Y., Ammit, A. J., & Panettieri, R. A. (2001). 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. Molecular Pharmacology, 60(4), 646-55.
Amrani Y, Ammit AJ, Panettieri RA. 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. Mol Pharmacol. 2001;60(4):646-55. PubMed PMID: 11562425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Amrani,Y, AU - Ammit,A J, AU - Panettieri,R A,Jr PY - 2001/9/20/pubmed PY - 2001/10/5/medline PY - 2001/9/20/entrez SP - 646 EP - 55 JF - Molecular pharmacology JO - Mol Pharmacol VL - 60 IS - 4 N2 - 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/11562425/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_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11562425 DB - PRIME DP - Unbound Medicine ER -