Activation of the TNFα-p55 Receptor Induces Myocyte Proliferation and Modulates Agonist-evoked Calcium Transients in Cultured Human Tracheal Smooth Muscle Cells

Yassine Amrani, Reynold A. Panettieri, Nelly Frossard, Christian Bronner

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Evidence suggests that cytokines may modulate smooth muscle cell function in a variety of inflammatory diseases. In the present study, we characterized the specific receptor subtypes that mediate tumor necrosis factor α (TNFα) effects on myocyte proliferation and on agonist-induced calcium transients in cultured human tracheal smooth muscle cells (TSMC). Pretreatment of human TSMC with TNFα potentiated cytosolic calcium [(Ca2+)i] transients evoked by carbachol. In a similar manner, selective TNFα-p55 receptor agonists such as htr-9, an activating monoclonal antibody, or a recombinant TNF-p55 (rTNF-p55), which specifically activates the TNFα-p55 receptor but not the TNFα-p75 receptor, also augmented [Ca2+]i transients evoked by carbachol. In parallel experiments, TNFα, rTNFα-p55, and htr-9 induced human TSMC proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Interestingly, activation of the TNFα-p75 receptor with a selective agonist, recombinant TNFα-p75 (rTNFα-p75), or inhibition of the TNFα-p75 receptor with utr-1, an inhibitory anti-TNFα-p75 receptor antibody, had no effect on TNFα-augmented calcium transients or on myocyte growth. To further confirm the receptor specificity of these findings, immunocytochemical studies were performed using receptor-specific antibodies. These studies demonstrated marked cell-surface expression of the TNFα-p55 receptor compared with expression of the TNFα-p75 receptor on human TSMC. Taken together, our results suggest that TNFα modulates agonist-induced calcium transients and induces human TSMC proliferation by specific activation of the TNFα-p55 receptor. Further studies addressing the cellular and molecular mechanisms regulating cytokine modulation of airway smooth muscle function may provide new insight into mechanisms that induce airway hyperresponsiveness in asthma.

Original languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume15
Issue number1
DOIs
StatePublished - 1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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