title: Pro-inflammatory signaling by Jun-N-terminal kinase in inflammatory bowel disease.
abstract: Since Jun-N-terminal kinase participates in intracellular signaling cascades resulting in inflammatory responses, inhibiting this pathway may represent a new treatment for inflammatory bowel disease including ulcerative colitis and Crohn's disease. However, the functional significance of the activation of this kinase in inflammatory bowel disease remains unclear. We investigated whether Jun-N-terminal kinase activation is increased in inflammatory bowel disease and analyzed the effects of SP600125, which decreases inflammatory cytokine synthesis by inhibiting the phosphorylation of this kinase. Phosphorylation of the kinase was examined in affected human colon using an enzyme-linked immunosorbent assay and immunohistochemistry. The effect of SP600125 on cytokine production was examined in cultures of patients' leukocytes and colonic tissue. Finally, rats received injection of SP600125 (30 mg/kg, s.c.) or vehicle twice daily 2 h before the induction of colitis with dextran sulfate sodium. SP600125 effects were determined observationally and histologically. Colonic tissue contained increased phosphorylated kinase in patients with inflammatory bowel disease with expression localized to the nucleus of epithelial and lamina propria mononuclear cells in lesions. Culturing mononuclear cells or colonic tissue with SP600125 down-regulated inflammatory cytokine production. Prophylactic treatment with SP600125 significantly reduced clinical and pathological scores in dextran sulfate sodium-treated rats. This first demonstration of the pathogenetic role of Jun-N-terminal kinase in the development of intestinal inflammation suggests that inhibiting its phosphorylation could benefit patients with inflammatory bowel disease.
authors.affiliation: Second Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan. ibd@med.kurume-u.ac.jp
authors.forename: Keiichi
authors.initials: K
authors.lastname: Mitsuyama
authors.forename: Asuka
authors.initials: A
authors.lastname: Suzuki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Tomiyasu
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsuruta
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Kitazaki
authors.forename: Teiko
authors.initials: T
authors.lastname: Takeda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Satoh
authors.forename: Brydon L
authors.initials: BL
authors.lastname: Bennett
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyonaga
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D000873:Anthracenes; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000873:Anthracenes; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases