IL-17A synergistically stimulates TNF-α-induced IL-8 production in human airway epithelial cells: A potential role in amplifying airway inflammation

ABSTRACT

Background: Recent reports have suggested an involvement of neutrophilic inflammation driven by interleukin (IL)-17 from Th17 cells, especially in severe, refractory asthma. It remains unknown about the possible interactions of this cytokine and other proinflammatory cytokines to direct neutrophilic airway inflammation. Materials and Methods: We evaluated the effects of IL-17A, IL-17E, and IL-17F in combination with other stimuli such as tumor necrosis factor (TNF) –α on the production and expression of IL-8 in human bronchial epithelial cells. We also studied their effects on other cytokine production. The possible role of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways was evaluated by specific inhibitors. We examined the effects of anti-asthma drugs, such as steroids or salmeterol. Results: IL-17A alone induced only a minimal effect on IL-8 expression. IL-17A, but not IL-17E or IL-17F, in combination with TNF-α showed a synergistic effect on IL-8 expression. Similar findings were found when combination with IL-1β and IL-17A were used, but such was not the case with lipopolysaccharide (LPS). In addition, we further found such synergy on GM-CSF production. The synergy with TNF-α and IL-17A was significantly inhibited by MAPKs inhibitors. Corticosteroids such as fluticasone propionate and dexamethasone, but not salmeterol, partially suppressed the IL-17A and TNF-α-induced IL-8 production. Conclusions: IL-17A in the combination with TNF-α or IL-1β showed a synergistic augmenting effect on IL-8 and GM-CSF production in human airway epithelial cells.

KEYWORDS:

• asthma
• corticosteroid
• IL-17
• neutrophil

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Notes on contributors

KH performed the experiments as a principal investigator. HW designed the experiments and selected each appropriate methodology. MN performed the experiments especially cytokine measurements and did statistical analysis. KN and TI prepared cell culture and helped qRT-PCR analysis. MS performed statistical analysis of data obtained from the experiments. YT and TK participated in the design of the study. ST and TY participated in MTT assay and did statistical analysis. TS, DK and HI participated in the study design and coordination and helped to draft the manuscript. HG and HT designed the whole study and complete a final draft of the manuscript.