Airway inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are associated with elevated expression of IL-32, a recently described cytokine that appears to play a critical role in inflammation. However, thus far, the regulation of pulmonary IL-32 production has not been fully established. We examined the expression of IL-32 by TNF-α in primary human lung fibroblasts. Human lung fibroblasts were cultured in the presence or absence of TNF-α and/or other cytokines/TLR ligands or various signaling molecule inhibitors to analyze the expression of IL-32 by quantitative RT-PCR and enzyme-linked immunosorbent assay. Next, activation of Akt and JNK signaling pathways were investigated by Western blot. IL-32 mRNA of 4 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 IFN-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 signaling pathways. Therefore, the TNF-α/IL-32 axis may be a potential therapeutic target for airway inflammatory diseases.

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