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

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Journal Article
Allergy: European Journal of Allergy and Clinical Immunology, 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-α) and interferon-gamma (IFN-γ) on ASM CD40 and OX40L expression. Methods: CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-α and/or IFN-γ 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-γ and TNF-α synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-γ reduced TNF-α-induced OX40L expression to a similar extent in both cell types. TNF-α and IFN-γ induced CD40 via nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-κB and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-κB, but these were not statistically significant. The reduced OX40L expression with TNF-α and IFN-γ 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-γ may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression. © 2009 Blackwell Munksgaard.
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