Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner.
IL-17A, IL-17F, and IL-25 belong to the IL-17 family of cytokines, and are well known to play important roles in the host defense against infection and inflammatory diseases. IL-17C, also a member of the IL-17 family, is highly expressed in the epithelium; however, the function and regulatory mechanism of IL-17C in airway epithelium remain poorly understood. In this study, we demonstrate that polyinosinic-polycytidylic acid (polyI:C), the ligand to Toll-like receptor 3, is a potent inducer of IL-17C mRNA and protein expression in primary normal human bronchial epithelial (NHBE) cells. IL-17C induction by polyI:C was both time dependent and dose dependent, and was attenuated by inhibitors of the Toll-IL-1 receptor domain-containing adaptor-inducing INF-β (TRIF)-NF-κB pathway, Pepinh-TRIF, BAY11, NF-κB inhibitor III, and NF-κB p65 small interfering RNA, suggesting that IL-17C expression is induced by polyI:C via the Toll-like receptor 3-TRIF-NF-κB pathway. Both IL-17C and polyI:C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human β-defensin (hBD) 2, colony-stimulating factor 3 (CSF3), and S100A12 in NHBE cells. Knockdown of IL-17 receptor (IL-17R) E, the specific receptor for IL-17C, using IL-17RE small interfering RNA, attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression, without any reduction of polyI:C-induced IL-17C expression, which suggest that IL-17C enhances hBD2, CSF, and S100A12 expression in an autocrine/paracrine manner in NHBE cells. Knockdown of IL-17C also decreased polyI:C-induced hBD2, CSF3, and S100A12 expression. Thus, our data demonstrate that IL-17C is an essential epithelial cell-derived cytokine that enhances mucosal host defense responses in a unique autocrine/paracrine manner in the airway epithelium.
1 Second Division, Department of Internal Medicine.
Hideki
H
Kusagaya
Tomoyuki
T
Fujisawa
Katsumasa
K
Yamanaka
Kazutaka
K
Mori
Dai
D
Hashimoto
Noriyuki
N
Enomoto
Naoki
N
Inui
Yutaro
Y
Nakamura
Reen
R
Wu
Masato
M
Maekawa
Takafumi
T
Suda
Kingo
K
Chida
D019898:Autocrine Communication / Q000276:immunology / Q000502:physiology*; D001980:Bronchi / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D019899:Paracrine Communication / Q000276:immunology / Q000502:physiology*; D011070:Poly I-C / Q000276:immunology / Q000378:metabolism; D016184:Receptors, Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D009418:S100 Proteins / Q000276:immunology / Q000378:metabolism; D000067616:S100A12 Protein; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism*; D023083:beta-Defensins / Q000276:immunology / Q000378:metabolism
C517047:CSF3R protein, human; D020381:Interleukin-17; D016184:Receptors, Colony-Stimulating Factor; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D023083:beta-Defensins; D016899:Interferon-beta; D011070:Poly I-C