Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner

Hideki Kusagaya, Tomoyuki Fujisawa, Katsumasa Yamanaka, Kazutaka Mori, Dai Hashimoto, Noriyuki Enomoto, Naoki Inui, Yutaro Nakamura, Reen Wu, Masato Maekawa, Takafumi Suda, Kingo Chida

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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-κ β pathway, Pepinh-TRIF, BAY11, NF-κ β inhibitor III, and NF-κ β p65 small interfering RNA suggesting that IL-17C expression is induced by polyI: C via the Toll-like receptor 3-TRIF-NF-κ β pathway. Both IL-17C and polyI: C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human b-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.

Original languageEnglish (US)
Pages (from-to)30-39
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number1
StatePublished - Jan 2014


  • Autocrine
  • Host defense
  • Human bronchial epithelial cell
  • IL-17C
  • Toll-like receptor

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry


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