IL-17 Markedly Up-Regulates β-Defensin-2 Expression in Human Airway Epithelium via JAK and NF-κB Signaling Pathways

Abstract

Using microarray gene expression analysis, we first observed a profound elevation of human β-defensin-2 (hBD-2) message in IL-17-treated primary human airway epithelial cells. Further comparison of this stimulation with a panel of cytokines (IL-1α, 1β, 2–13, and 15–18; IFN-γ; GM-CSF; and TNF-α) demonstrated that IL-17 was the most potent cytokine to induce hBD-2 message (>75-fold). IL-17-induced stimulation of hBD-2 was time and dose dependent, and this stimulation also occurred at the protein level. Further studies demonstrated that hBD-2 stimulation was attenuated by IL-17R-specific Ab, but not by IL-1R antagonist or the neutralizing anti-IL-6 Ab. This suggests an IL-17R-mediated signaling pathway rather than an IL-17-induced IL-1αβ and/or IL-6 autocrine/paracrine loop. hBD-2 stimulation was sensitive to the inhibition of the JAK pathway, and to the inhibitors that affect NF-κB translocation and the DNA-binding activity of its p65 NF-κB subunit. Transient transfection of airway epithelial cells with an hBD-2 promoter-luciferase reporter gene expression construct demonstrated that IL-17 stimulated promoter-reporter gene activity, suggesting a transcriptional mechanism for hBD-2 induction. These results support an IL-17R-mediated signaling pathway involving JAK and NF-κB in the transcriptional stimulation of hBD-2 gene expression in airway epithelium. Because IL-17 has been identified in a number of airway diseases, especially diseases related to microbial infection, these findings provide a new insight into how IL-17 may play an important link between innate and adaptive immunity, thereby combating infection locally within the airway epithelium.

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma

“…Other potential roles of IL-17A in asthmatic airways might include the stimulation of mucus cell differentiation 25,41 and induction of chemokine and nitric oxide release. 22,23,30,42 Our study suggests that coexistence of T H 2 cytokines and IL-17A might have a significant effect on the pathogenesis of asthma by positively modulating the existing T (Fig 6, B and C). However, STAT6 nuclear translocation and IL-19 promoter binding were similar in IL-13-and IL-13/IL-17A-treated cells, despite the fact that IL-17A/IL-13-cotreated cells express much higher IL-19 compared with IL-13 alone.…”

“…SYBR Greenbased real-time PCR was used to quantify the gene of interest, as described previously. 19,23 Relative expressions of genes of interest were normalized to glyceraldehyde-3-phosphate dehydrogenase or β-actin transcripts.…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…As intestinal Th17 cells have an important role in antimicrobial immunity, particularly at mucosal sites (88)(89)(90), as well as in sustaining enterocyte homeostasis (89,90), the preferential depletion of Th17 cells in pathogenic HIV/SIV infections may be involved in the damage to the structural and functional integrity of the intestinal barrier and in the loss of control over microbial translocation. Indeed, Favre et al elegantly demonstrated that the early loss of GI Th17 in pathogenic SIV infection is associated with overt signs of disease progression that include enhanced immune activation and T-cell apoptosis, increased levels of circulating alpha interferon (IFN-␣), enhanced transcription of IFN-␣-induced genes, and rapid CD4 ϩ T-lymphocyte depletion (87).…”

Th17 cells: new players in asthma pathogenesis

“…The other IL-17 family members, IL-17B, IL-17C, IL-17D, and IL-17E, are produced by non-T-cell sources. Because of these properties, the main function of Th17 has thought to be the clearance of extracellular pathogens (10,11).…”