IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice

Manabu Shiraki, Hiroyuki Aihara, Yoshitaka Kinouchi, Seiichi Takahashi, Motoji Oki, Mitsunori Noguchi, Kazuma Takahashi, Jun Ichi Miyazaki, Toru Shimosegawa

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14 Citations (Scopus)

Abstract

T-helper-1 (Th1) cytokines play an important role in Crohn's disease, and interleukin-12 (IL-12), which is composed of two subunits, p40 and p35, drives Th1 differentiation. In previous reports, IL-12 p40 was shown to prevent IL-12 from binding to the receptor. We demonstrate here the effect of IL-12 p40 overexpression in intestinal epithelia on enterocolitis mediated by Th1 cells in IL-10-deficient (IL-10-/-) mice on a C57BL/6J background. IL-10 deficient (IL-10-/-)/T3b-IL-12 p40+ (IL-12 p40+) mice and IL-10-/-/T3b-IL-12 p40 - (IL-12 p40-) mice were generated by crossing T3 b-IL-12 p40 transgenic mice and IL-10-/- mice. At 8 weeks of age, IL-12 p40+ mice did not show any clinical manifestations of colitis. The colon length of IL-12 p40- mice became shorter than that of IL-12 p40+ mice. The histological score of IL-12 p40+ mice was lower. Interferon-gamma (IFN-γ) production was suppressed in both the mesenteric lymph node cell culture and colon tissue culture of IL-12 p40+ mice. There was no significant difference in IL-4 production and tumor necrosis factor-alpha (TNF-α) production between the two groups. These results show that overexpression of IL-12 p40 in intestinal epithelia prevents enterocolitis in IL-10-/- mice by suppressing IFN-γ production, and suggest a potential clinical application of IL-12 p40 for Crohn's disease. Furthermore, these results also suggest that local gene transduction in the intestinal epithelium may be a potent therapeutic approach for Crohn's disease.

Original languageEnglish
Pages (from-to)1491-1500
Number of pages10
JournalLaboratory Investigation
Volume84
Issue number11
DOIs
Publication statusPublished - 2004 Nov 1

Keywords

  • IL-10-deficient-mice
  • IL-12 p40
  • Th1 cytokine

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Shiraki, M., Aihara, H., Kinouchi, Y., Takahashi, S., Oki, M., Noguchi, M., Takahashi, K., Miyazaki, J. I., & Shimosegawa, T. (2004). IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice. Laboratory Investigation, 84(11), 1491-1500. https://doi.org/10.1038/labinvest.3700175