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Molecular Pharmacology

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Research ArticleArticle

Tumor Necrosis Factor Receptor (TNFR) 1, but Not TNFR2, Mediates Tumor Necrosis Factor-α–Induced Interleukin-6 and RANTES in Human Airway Smooth Muscle Cells: Role of p38 and p42/44 Mitogen-Activated Protein Kinases

Yassine Amrani, Alaina J. Ammit and Reynold A. Panettieri Jr.
Molecular Pharmacology October 2001, 60 (4) 646-655;
Yassine Amrani
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Alaina J. Ammit
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Reynold A. Panettieri Jr.
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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-α (TNFα)-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 TNFα-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 TNFα-induced RANTES or IL-6 secretion. SB203580 and PD98059 had little effect on TNFα-induced nuclear factor-κB (NF-κB) activation as determined in cells transfected with a NF-κB–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-κB-mediated gene transcription. Using receptor-specific blocking antibodies, we found that TNFR1 primarily regulates TNFα-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 TNFα-induced synthetic functions in ASM cells.

Footnotes

  • This work was supported by Grants R01-HL64063 and R01-HL55301 from the National Institutes of Health. A.J.A. was supported by a C. J. Martin Fellowship (977301) from the National Health and Medical Research Council (Australia).

  • Abbreviations:
    ASM
    airway smooth muscle
    TNFα
    tumor necrosis factor-α
    MAPK
    mitogen-activated protein kinase
    ERK
    extracellular signal-regulated kinase
    IL
    interleukin
    PDGF
    platelet-derived growth factor
    ICAM-1
    intercellular adhesion molecule-1
    RANTES
    regulated on activation, normal T-cell expressed and secreted
    NF-κB
    nuclear factor-κB
    FBS
    fetal bovine serum
    BSA
    bovine serum albumin
    COX
    cyclooxygenase
    • Received February 15, 2001.
    • Accepted June 21, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Tumor Necrosis Factor Receptor (TNFR) 1, but Not TNFR2, Mediates Tumor Necrosis Factor-α–Induced Interleukin-6 and RANTES in Human Airway Smooth Muscle Cells: Role of p38 and p42/44 Mitogen-Activated Protein Kinases
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Research ArticleArticle

Tumor Necrosis Factor Receptor (TNFR) 1, but Not TNFR2, Mediates Tumor Necrosis Factor-α–Induced Interleukin-6 and RANTES in Human Airway Smooth Muscle Cells: Role of p38 and p42/44 Mitogen-Activated Protein Kinases

Yassine Amrani, Alaina J. Ammit and Reynold A. Panettieri
Molecular Pharmacology October 1, 2001, 60 (4) 646-655;

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Research ArticleArticle

Tumor Necrosis Factor Receptor (TNFR) 1, but Not TNFR2, Mediates Tumor Necrosis Factor-α–Induced Interleukin-6 and RANTES in Human Airway Smooth Muscle Cells: Role of p38 and p42/44 Mitogen-Activated Protein Kinases

Yassine Amrani, Alaina J. Ammit and Reynold A. Panettieri
Molecular Pharmacology October 1, 2001, 60 (4) 646-655;
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