Collagen XVII (BP180) modulates keratinocyte expression of the proinflammatory chemokine, IL-8

Exp Dermatol. 2012 Aug;21(8):605-11. doi: 10.1111/j.1600-0625.2012.01529.x.

Abstract

Collagen XVII (COL17), a transmembrane protein expressed in epidermal keratinocytes (EK), is targeted by pathogenic autoantibodies in bullous pemphigoid. Treatment of EK with anti-COL17 autoantibodies triggers the production of proinflammatory cytokines. In this study, we test the hypothesis that COL17 is involved in the regulation of the EK proinflammatory response, using IL-8 expression as the primary readout. The absence of COL17 in EK derived from a junctional epidermolysis bullosa patient or shRNA-mediated knockdown of COL17 in normal EK resulted in a dysregulation of IL-8 responses under various conditions. The COL17-deficient cells showed an abnormally high IL-8 response after treatment with lipopolysaccharide (LPS), ultraviolet-B radiation or tumor necrosis factor, but exhibited a blunted IL-8 response to phorbol 12-myristate 13-acetate exposure. Induction of COL17 expression in COL17-negative EK led to a normalization of the LPS-induced proinflammatory response. Although α6β4 integrin was found to be up-regulated in COL17-deficient EK, siRNA-mediated knockdown of the α6 and β4 subunits revealed that COL17's effects on the LPS IL-8 response are not dependent on this integrin. In LPS-treated cells, inhibition of NF-kappa B activity in COL17-negative EK resulted in a normalization of their IL-8 response, and expression of an NF-kappa B-driven reporter was shown to be higher in COL17-deficient, compared with normal EK. These findings support the hypothesis that COL17 plays an important regulatory role in the EK proinflammatory response, acting largely via NF-kappa B. Future investigations will focus on further defining the molecular basis of this novel control network.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Cell Line
  • Collagen Type XVII
  • Epidermolysis Bullosa / metabolism*
  • Epidermolysis Bullosa / pathology
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Integrin alpha6beta4 / metabolism
  • Interleukin-18 / metabolism*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Keratinocytes / radiation effects
  • Lipopolysaccharides / pharmacology
  • NF-kappa B / metabolism
  • Non-Fibrillar Collagens / deficiency
  • Non-Fibrillar Collagens / genetics
  • Non-Fibrillar Collagens / metabolism*
  • RNA, Small Interfering / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ultraviolet Rays

Substances

  • Autoantigens
  • Integrin alpha6beta4
  • Interleukin-18
  • Lipopolysaccharides
  • NF-kappa B
  • Non-Fibrillar Collagens
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Tetradecanoylphorbol Acetate