CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscle

Wiley-Blackwell Publishing Ltd.
Publication Type:
Journal Article
Allergy, 2009, 64 (7), pp. 1074 - 1082
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Background: CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-?) on ASM CD40 and OX40L expression. Methods: CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-a and/or IFN-? was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. Results: Interferon-? and TNF-a synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-? reduced TNF-a-induced OX40L expression to a similar extent in both cell types. TNF-a and IFN-? induced CD40 via nuclear factor-?B (NF-?B) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-?B and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-?B, but these were not statistically significant. The reduced OX40L expression with TNF-a and IFN-? involved extracellular regulated kinase 1/2 activation. Conclusion: Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-? may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.
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