c-Jun N-terminal kinase and Akt signalling pathways regulating tumour necrosis factor-α-induced interleukin-32 expression in human lung fibroblasts: implications in airway inflammation.
Airway inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are associated with elevated expression of interleukin-32 (IL-32), a recently described cytokine that appears to play a critical role in inflammation. However, so far, the regulation of pulmonary IL-32 production has not been fully established. We examined the expression of IL-32 by tumour necrosis factor-α (TNF-α) in primary human lung fibroblasts. Human lung fibroblasts were cultured in the presence or absence of TNF-α and/or other cytokines/Toll-like receptor (TLR) ligands or various signalling molecule inhibitors to analyse the expression of IL-32 by quantitative RT-PCR and ELISA. Next, activation of Akt and c-Jun N-terminal kinase (JNK) signalling pathways was investigated by Western blot. Interleukin-32 mRNA of four spliced isoforms (α, β, γ and δ) was up-regulated upon TNF-α stimulation, which was associated with a significant IL-32 protein release from TNF-α-activated human lung fibroblasts. The combination of interferon-γ and TNF-α induced enhanced IL-32 release in human lung fibroblasts, whereas IL-4, IL-17A, IL-27 and TLR ligands did not alter IL-32 release in human lung fibroblasts either alone, or in combination with TNF-α. Furthermore, the activation of Akt and JNK pathways regulated TNF-α-induced IL-32 expression in human lung fibroblasts, and inhibition of the Akt and JNK pathways was able to suppress the increased release of IL-32 to nearly the basal level. These data suggest that TNF-α may be involved in airway inflammation via the induction of IL-32 by activating Akt and JNK signalling pathways. Therefore, the TNF-α/IL-32 axis may be a potential therapeutic target for airway inflammatory diseases.
['Li|Dagen|D|', 'Chen|Dapeng|D|', 'Zhang|Xuemei|X|', 'Wang|Hong|H|', 'Song|Zixin|Z|', 'Xu|Wenchun|W|', 'He|Yujuan|Y|', 'Yin|Yibing|Y|', 'Cao|Ju|J|']
D001249:Asthma D002478:Cells, Cultured D005347:Fibroblasts D006801:Humans D007249:Inflammation D007371:Interferon-gamma D020381:Interleukin-17 D015847:Interleukin-4 D007378:Interleukins D048031:JNK Mitogen-Activated Protein Kinases D008168:Lung D020033:Protein Isoforms D051057:Proto-Oncogene Proteins c-akt D029424:Pulmonary Disease, Chronic Obstructive D012333:RNA, Messenger D011994:Recombinant Proteins D051193:Toll-Like Receptors D014409:Tumor Necrosis Factor-alpha D015854:Up-Regulation
fibroblasts inflammation cytokines