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Requirement for Both JAK-Mediated PI3K Signaling and ACT1/TRAF6/TAK1-Dependent NF-B Activation by IL-17A in Enhancing Cytokine Expression in Human Airway Epithelial Cells¹

Center for Comparative Respiratory Biology and Medicine, University of California, Davis, CA 95616

Through DNA microarray analysis and quantitative PCR verification, we have identified additional IL-17A-inducible genes—IL-19, CXCL-1, -2, -3, -5, and -6—in well-differentiated normal human bronchial epithelial cells. These genes, similar to previously described human β-defensin-2 (HBD-2) and CCL-20, were induced by a basolateral treatment of IL-17A, and regulated by PI3K signaling and NF-B activation. For PI3K signaling, increases of cellular PIP₃ and phosphorylation of downstream molecules, such as Akt and glycogen synthase kinase-3β (GSK3β) (S9), were detected. Induced gene expression and HBD-2 promoter activity were attenuated by LY294002, p110 small-interfering RNA (siRNA), as well as by an overexpression of constitutively active GSK3β(S9A) or wild-type phosphatase and tensin homolog. Increased phosphorylation of JAK1/2 after IL-17A treatment was detected in primary normal human bronchial epithelium cells. Transfected siRNAs of JAK molecules and JAK inhibitor I decreased IL-17A-induced gene expression and GSK3β(S9) phosphorylation. However, both JAK inhibitor I and PI3K inhibitor had no effect on the DNA-binding activities of p65 and p50 to NF-B consensus sequences. This result suggested a JAK-associated PI3K signaling axis is independent from NF-B activation. With siRNA to knockdown STIR (similar expression to fibroblast growth factor and IL-17R; Toll-IL-1R)-related signaling molecules, such as Act1, TNFR-associated factor 6 (TRAF6), and TGF-β-activated kinase 1 (TAK1), and transfection of A52R, an inhibitor of the MyD88/TRAF6 complex, or dominant-negative TAK1, IL-17A-inducible gene expression and HBD-2 promoter activity were reduced. Additionally, IL-17A-induced p65 and p50 NF-B activations were confirmed and their nuclear translocations were down-regulated by siRNAs of TRAF6 and TAK1. These results suggest that two independent and indispensable signaling pathways—1) JAK1-associated PI3K signaling and 2) Act1/TRAF6/TAK1-mediated NF-B activation—are stimulated by IL-17A to regulate gene induction in human airway epithelial cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from National Institutes of Health (HL077902, HL077315, and ES00628) and T32 HL07103 (to P.T.).

² Address correspondence and reprint requests to Dr. Reen Wu, Center for Comparative Respiratory Biology and Medicine, University of California, Genome and Biomedical Science Facility, Suite 6510, 451 East Health Science Drive, Davis, CA 95616. E-mail address: rwu{at}ucdavis.edu

³ Abbreviations used in this paper: HBD-2, human β-defensin-2; GRO, growth-related oncogene; GCP, granulocyte chemotactic protein; TIR, Toll-IL-1R; SEFIR, similar expression of fibroblast growth factor and IL-17R; STIR, SEFIR and Toll-IL-1R; TRAF6, TNFR-associated factor 6; TAK1, TGF-β-activated kinase 1; NHBE, normal human bronchial epithelium; siRNA, small-interfering RNA; wt, wild type; PTEN, phosphatase and tensin homolog; mut, mutant; ca, constitutively active; Ct, threshold cycle; GSK3β, glycogen synthase kinase-3β; RO, random oligomer.

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