Ahlawat Sarita, Xie Fang, Zhu Yi, D'Hondt Rebecca, Ding Xinxin, Zhang Qing-Yu, Mantis Nicholas J
1] Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY [2].
1] Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, NY [2].
Sci Rep. 2014 Jul 3;4:5551. doi: 10.1038/srep05551.
Cytochrome P450 (P450) enzymes are a superfamily of heme-containing enzymes involved in the metabolism of various endogenous compounds, including retinoids, glucocorticoids, and eicosanoids, that are postulated to participate in the maintenance and/or development of inflammatory and immune reactions in the intestinal mucosa. To investigate the role of P450 enzymes in intestinal inflammation and immunity, we took advantage of IE-Cpr-null mice, which are deficient in intestinal epithelium of NADPH-cytochrome P450 reductase (CPR), the obligate redox partner of all microsomal P450 enzymes. We report that IE-Cpr-null mice, following an acute toxin challenge, had higher levels of pro-inflammatory chemokines and increased tissue damage compared to wild-type mice. IE-Cpr-null mice had normal Peyer's patch numbers and elicited normal secretory IgA (SIgA) responses. However, SIgA baseline levels in IE-Cpr-null mice were consistently elevated over WT littermates. While neither retinoic acid nor glucocorticoid levels in serum and intestinal homogenates were altered in IE-Cpr-null mice, basal levels of arachidonic acid metabolites (11,12-DiHETE and 14,15-DiHETE) with known anti-inflammatory property were significantly lower compared to WT controls. Overall, these findings reveal immunological and metabolic changes resulting from a genetic deficiency in CPR expression in the intestine, and support a role for microsomal P450 enzymes in mucosal homeostasis and immunity.
细胞色素P450（P450）酶是一类含血红素的酶超家族，参与多种内源性化合物的代谢，包括类视黄醇、糖皮质激素和类花生酸，据推测它们参与肠道黏膜炎症和免疫反应的维持及/或发展。为了研究P450酶在肠道炎症和免疫中的作用，我们利用了IE-Cpr基因敲除小鼠，这些小鼠的肠道上皮缺乏NADPH-细胞色素P450还原酶（CPR），而CPR是所有微粒体P450酶的必需氧化还原伴侣。我们报告称，与野生型小鼠相比，IE-Cpr基因敲除小鼠在急性毒素攻击后，促炎趋化因子水平更高，组织损伤增加。IE-Cpr基因敲除小鼠的派尔集合淋巴结数量正常，分泌型IgA（SIgA）反应正常。然而，IE-Cpr基因敲除小鼠的SIgA基线水平始终高于野生型同窝小鼠。虽然IE-Cpr基因敲除小鼠血清和肠道匀浆中的视黄酸和糖皮质激素水平均未改变，但与野生型对照组相比，具有已知抗炎特性的花生四烯酸代谢物（11,12-二氢二十碳四烯酸和14,15-二氢二十碳四烯酸）的基础水平显著降低。总体而言，这些发现揭示了肠道中CPR表达基因缺陷导致的免疫和代谢变化，并支持微粒体P450酶在黏膜稳态和免疫中的作用。
