Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection
Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection
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DOI：
10.1152/ajpgi.90365.2008
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发表时间：
2008-11-01
影响因子：
4.5
通讯作者：
Kiela, P. R.
中科院分区：
文献类型：
--
作者：
Larmonier, C. B.;Uno, J. K.;Kiela, P. R.
姜黄素（二黄菊基甲烷）在体外肠上皮细胞（IEC）和免疫细胞中表现出深刻的抗炎作用，并在化学诱导的结肠炎的啮齿动物模型中表现出保护作用，其推测的主要作用机制是通过抑制NF-κ B。B。虽然姜黄素已被证明可有效降低溃疡性结肠炎患者的复发率，但尚未评估姜黄素在克罗恩病（CD）或Th-1/Th-17介导的CD免疫模型中的有效性。因此，我们研究了饮食中姜黄素（0.1-1%）对结肠炎发展、免疫激活和无菌IL-10（-/-）或IL-10（-/-）; NF-κ B（EGFP）小鼠体内NF-κ B（B）活性的影响。近端和远端结肠形态显示仅在0.1%的姜黄素具有轻度保护作用。结肠IFN-gamma和IL-12/23 p40 mRNA表达遵循相似的模式（类似于0.1%时的50%抑制）。在IL-10（-/-）小鼠中，结肠外植体和肠系膜淋巴结细胞分泌IL-12/23 p40和IFN-γ升高，并且饮食姜黄素不会降低。令人惊讶的是，姜黄素没有明显抑制IL-10（-/-）小鼠（磷酸化NF-κ Bp 65）或IL-10（-/-）; NF-κ B（EGFP）小鼠（全器官或共聚焦成像）中NF-κ B的活化。此外，我们证明IL-10和姜黄素协同作用，下调IEC中的NF-κ B活性以及脾细胞和树突状细胞产生IL-12/23 p40。总之，姜黄素对IL-10（-/-）小鼠Th-1介导的结肠炎的有效性有限，结肠形态得到适度改善，但对致病性T细胞应答和原位NF-κ B活性无显著影响。体外研究表明，姜黄素的保护作用是IL-10依赖性的。
Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro and exhibits a protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-kappa B. Although it has been demonstrated effective in reducing relapse rate in ulcerative colitis patients, curcumin's effectiveness in Crohn's disease (CD) or in Th-1/Th-17 mediated immune models of CD has not been evaluated. Therefore, we investigated the effects of dietary curcumin (0.1-1%) on the development of colitis, immune activation, and in vivo NF-kappa B activity in germ-free IL-10(-/-) or IL-10(-/-); NF-kappa B(EGFP) mice colonized with specific pathogen-free microflora. Proximal and distal colon morphology showed a mild protective effect of curcumin only at 0.1%. Colonic IFN-gamma and IL-12/23p40 mRNA expression followed similar pattern (similar to 50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN-gamma by colonic explants and mesenteric lymph node cells was elevated in IL-10(-/-) mice and was not decreased by dietary curcumin. Surprisingly, activation of NF-kappa B in IL-10(-/-) mice (phospho-NF-kappa Bp65) or in IL-10(-/-); NF-kappa B(EGFP) mice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to downregulate NF-kappa B activity in IEC and IL-12/23p40 production by splenocytes and dendritic cells. In conclusion, curcumin demonstrates limited effectiveness on Th-1 mediated colitis in IL-10(-/-) mice, with moderately improved colonic morphology, but with no significant effect on pathogenic T cell responses and in situ NF-kappa B activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent.