GRO-α regulation in airway smooth muscle by IL-1β and TNF-α: Role of NF-κB and MAP kinases

Razao Issa, Shaoping Xie, Kang Yun Lee, Rex D. Stanbridge, Pankaj Bhavsar, Maria B. Sukkar, Kian Fan Chung

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54 Citations (Scopus)

Abstract

Airway smooth muscle cells (ASMC) are a source of inflammatory chemokines that may propagate airway inflammatory responses. We investigated the production of the CXC chemokine growth-related oncogene protein-α (GRO-α) from ASMC induced by cytokines and the role of MAPK and NF-κB pathways. ASMC were cultured from human airways, grown to confluence, and exposed to cytokines IL-1β and TNF-α after growth arrest. GRO-α release, measured by ELISA, was increased by >50-fold after IL-1β (0.1 ng/ml) or 5-fold after TNF-α (1 ng/ml) in a dose- and time-dependent manner. GRO-α release was not affected by the T helper type 2 cytokines IL-4, IL-10, and IL-13. IL-1β and TNF-α also induced GRO-α mRNA expression. Supernatants from IL-1β-stimulated ASMC were chemotactic for neutrophils; this effect was inhibited by anti-GRO-α blocking antibody. AS-602868, an inhibitor of IKK-2, and PD-98059, an inhibitor of ERK, inhibited GRO-α release and mRNA expression, whereas SP-600125, an inhibitor of JNK, reduced GRO-α release without effect on mRNA expression. SB-203580, an inhibitor of p38 MAPK, had no effect. AS-602868 but not PD-98059 or SP-600125 inhibited p65 DNA-binding induced by IL-1β and TNF-α. By chromatin immunoprecipitation assay, IL-1β and TNF-α enhanced p65 binding to the GRO-α promoter, which was inhibited by AS-602868. IL-1β- and TNF-α-stimulated expression of GRO-α from ASMC is regulated by independent pathways involving NF-κB activation and ERK and JNK pathways. GRO-α released from ASMC participates in neutrophil chemotaxis.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume291
Issue number1
DOIs
Publication statusPublished - 2006
Externally publishedYes

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Keywords

  • c-Jun NH-terminal kinase
  • Extracellular signal-regulated kinase
  • Growth-related oncogene protein-α
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

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