ASK1 promotes the contact hypersensitivity response through IL-17 production

Sci Rep. 2014 Apr 16:4:4714. doi: 10.1038/srep04714.

Abstract

Contact hypersensitivity (CHS) is a form of delayed-type hypersensitivity triggered by the response to reactive haptens (sensitization) and subsequent challenge (elicitation). Here, we show that ASK1 promotes CHS and that suppression of ASK1 during the elicitation phase is sufficient to attenuate CHS. ASK1 knockout (KO) mice exhibited impaired 2,4-dinitrofluorobenzene (DNFB)-induced CHS. The suppression of ASK1 activity during the elicitation phase through a chemical genetic approach or a specific inhibitory compound significantly reduced the CHS response to a level similar to that observed in ASK1 KO mice. The reduced response was concomitant with the strong inhibition of production of IL-17, a cytokine that plays an important role in CHS and other inflammatory diseases, from sensitized lymph node cells. These results suggest that ASK1 is relevant to the overall CHS response during the elicitation phase and that ASK1 may be a promising therapeutic target for allergic contact dermatitis and other IL-17-related inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Dermatitis, Contact / genetics*
  • Dermatitis, Contact / metabolism
  • Dermatitis, Contact / pathology
  • Dinitrofluorobenzene / toxicity
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • MAP Kinase Kinase Kinase 5 / deficiency
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Interleukin-17
  • Interferon-gamma
  • Dinitrofluorobenzene
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse