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GRO- regulation in airway smooth muscle by IL-1 and TNF-: role of NF-B and MAP kinases

¹Experimental Studies, National Heart and Lung Institute, Imperial College, and ²Cardiothoracic Surgery, St. Mary's Hospital, London, United Kingdom

Submitted 8 September 2005 ; accepted in final form 6 December 2005

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- (GRO-) from ASMC induced by cytokines and the role of MAPK and NF-B pathways. ASMC were cultured from human airways, grown to confluence, and exposed to cytokines IL-1 and TNF- after growth arrest. GRO- release, measured by ELISA, was increased by >50-fold after IL-1 (0.1 ng/ml) or 5-fold after TNF- (1 ng/ml) in a dose- and time-dependent manner. GRO- release was not affected by the T helper type 2 cytokines IL-4, IL-10, and IL-13. IL-1 and TNF- also induced GRO- mRNA expression. Supernatants from IL-1-stimulated ASMC were chemotactic for neutrophils; this effect was inhibited by anti-GRO- blocking antibody. AS-602868, an inhibitor of IKK-2, and PD-98059, an inhibitor of ERK, inhibited GRO- release and mRNA expression, whereas SP-600125, an inhibitor of JNK, reduced GRO- 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-1 and TNF-. By chromatin immunoprecipitation assay, IL-1 and TNF- enhanced p65 binding to the GRO- promoter, which was inhibited by AS-602868. IL-1- and TNF--stimulated expression of GRO- from ASMC is regulated by independent pathways involving NF-B activation and ERK and JNK pathways. GRO- released from ASMC participates in neutrophil chemotaxis.

growth-related oncogene protein-; extracellular signal-regulated kinase; c-Jun NH₂-terminal kinase; nuclear factor-B

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