IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

Eur J Immunol. 2007 Feb;37(2):338-50. doi: 10.1002/eji.200636420.

Abstract

IL-18 is involved in the pathogenesis of atopic dermatitis, psoriasis, and allergic contact dermatitis. CXCL9, CXCL10, and CXCL11 recruit type 1 T cells, and the production of these chemokines by keratinocytes is enhanced in these dermatoses. We examined the in vitro effects of IL-18 on IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in human keratinocytes. IL-18 enhanced the IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of NF-kappaB, STAT1, and IFN-regulatory factor (IRF)-1. Antisense oligonucleotides against NF-kappaB p50, p65, or STAT1 suppressed CXCL9, CXCL10, and CXCL11 production, and antisense IRF-1 suppressed CXCL11 production. Inhibitors of PI3 K, p38 MAPK, and MEK suppressed IL-18 plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappaB, STAT1, and IRF-1 activities. IL-18 induced phosphorylation of ERK and Akt, while IFN-gamma induced phosphorylation of p38 MAPK. These results suggest that IL-18 may potentiate IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes by activating NF-kappaB, STAT1, or IRF-1 through PI3 K/Akt and MEK/ERK pathways. These effects of IL-18 may promote the infiltration of type 1 T cells into lesions with inflammatory dermatoses and amplify the skin inflammation. IL-18 may act as a pro-inflammatory cytokine in these dermatoses and thus is a candidate therapeutic target.

MeSH terms

  • Cells, Cultured
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CXC / immunology
  • Chemokines, CXC / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Interferon Regulatory Factor-1 / immunology
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism*
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism*
  • Keratinocytes / immunology
  • Keratinocytes / metabolism*
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / immunology
  • Transfection
  • Up-Regulation

Substances

  • CXCL11 protein, human
  • CXCL9 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Chemokines, CXC
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interleukin-18
  • NF-kappa B
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferon-gamma