IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways.
Using microarray gene expression analysis, we first observed a profound elevation of human beta-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-1alpha, 1beta, 2-13, and 15-18; IFN-gamma; GM-CSF; and TNF-alpha) 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-1alphabeta 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-kappaB translocation and the DNA-binding activity of its p65 NF-kappaB 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-kappaB 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.
Kao
Cheng-Yuan
CY
Center for Comparative Respiratory Biology and Medicine, University of California, Davis, CA 95616, USA.
Chen
Yin
Y
Thai
Philip
P
Wachi
Shinichiro
S
Huang
Fei
F
Kim
Christy
C
Harper
Richart W
RW
Wu
Reen
R
D000818:Animals; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012137:Respiratory System / Q000201:enzymology / Q000378:metabolism*; D015854:Up-Regulation; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics*
C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D020381:Interleukin-17; D016328:NF-kappa B; D023083:beta-Defensins; D011505:Protein-Tyrosine Kinases