title: 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.
abstract: 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.
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, China.
authors.forename: Dagen
authors.initials: D
authors.lastname: Li
authors.forename: Dapeng
authors.initials: D
authors.lastname: Chen
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Zixin
authors.initials: Z
authors.lastname: Song
authors.forename: Wenchun
authors.initials: W
authors.lastname: Xu
authors.forename: Yujuan
authors.initials: Y
authors.lastname: He
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yin
authors.forename: Ju
authors.initials: J
authors.lastname: Cao
mesh_terms: D001249:Asthma / Q000276:immunology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008168:Lung / Q000166:cytology; D020033:Protein Isoforms / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C508717:IL17A protein, human; C496971:IL32 protein, human; C508598:IL4 protein, human; D020381:Interleukin-17; D007378:Interleukins; C464565:MYDGF protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: cytokines; fibroblasts; inflammation