The specific JNK inhibitor SP600125 targets tumour necrosis factor-α production and epithelial cell apoptosis in acute murine colitis

Kiran Assi, Rex Pillai, Antonio Gómez-Muñoz, David Owen, Baljinder Salh

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Stress-activated protein kinases (SAPKs) are activated in human inflammatory bowel disease (IBD). Recently it has been demonstrated that p38MAPK (mitogen-activated protein kinase) inhibition using SB203580 is effective in reducing disease in both dextran sulphate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced q2murine colitides, underscoring the importance of this pathway in gastrointestinal inflammation. However, the contribution of c-Jun N-terminal kinase (JNK) in intestinal inflammation is unknown. Based on the known involvement of JNK in tumour necrosis factor-α (TNF-α) expression and in mediating the effects of oxidant stress, we hypothesized that JNK inhibition would also affect colitis. Our studies in mice with DSS-induced colitis treated with the JNK inhibitor SP600125, indicate that there is a significant reduction in wasting as well as a significant reduction in histological damage scores. Both total colonic and mesenteric lymphocyte CD3/CD28-stimulated TNF-α levels were dramatically reduced under the same circumstances. This was associated with a reduction in JNK protein expression and activity, as well as a reduction in AP-1 DNA binding with SP600125. Interestingly, there were no apparent changes in either p38MAPK or p42/44ERKs. Immunofluorescence of the colon for the active form of JNK revealed a prominent signal arising from the infiltrating inflammatory cells. SP600125 reduced this as well as, specifically, macrophage infiltration. Strikingly, we also demonstrate reduced epithelial cell apoptosis in response to treatment with SP600125. We conclude that specific inhibition of JNK is beneficial in the DSS model of colitis, and may be of value in human IBD.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalImmunology
Volume118
Issue number1
DOIs
StatePublished - May 1 2006
Externally publishedYes

Keywords

  • Cytokines
  • Dextran sulphate sodium
  • Inflammatory bowel disease
  • Mitogen-activated protein kinase
  • SP600125

ASJC Scopus subject areas

  • Immunology

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