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Collagen XVII ( BP 180) modulates keratinocyte expression of the proinflammatory chemokine, IL ‐8
Author(s) -
den Bergh Françoise,
Eliason Steven L.,
Burmeister Brian T.,
Giudice George J.
Publication year - 2012
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.1600-0625.2012.01529.x
Subject(s) - proinflammatory cytokine , chemokine , tumor necrosis factor alpha , chemistry , lipopolysaccharide , microbiology and biotechnology , immunology , gene knockdown , keratinocyte , inflammation , biology , in vitro , biochemistry , apoptosis
Collagen XVII ( COL 17), a transmembrane protein expressed in epidermal keratinocytes ( EK ), is targeted by pathogenic autoantibodies in bullous pemphigoid. Treatment of EK with anti‐ COL 17 autoantibodies triggers the production of proinflammatory cytokines. In this study, we test the hypothesis that COL 17 is involved in the regulation of the EK proinflammatory response, using IL ‐8 expression as the primary readout. The absence of COL 17 in EK derived from a junctional epidermolysis bullosa patient or sh RNA ‐mediated knockdown of COL 17 in normal EK resulted in a dysregulation of IL ‐8 responses under various conditions. The COL 17‐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 COL 17 expression in COL 17‐negative EK led to a normalization of the LPS ‐induced proinflammatory response. Although α6β4 integrin was found to be up‐regulated in COL 17‐deficient EK , si RNA ‐mediated knockdown of the α6 and β4 subunits revealed that COL 17'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 COL 17‐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 COL 17‐deficient, compared with normal EK . These findings support the hypothesis that COL 17 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.