Department of Internal Medicine, Division of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Infect Immun. 2012 Feb;80(2):753-67. doi: 10.1128/IAI.06101-11. Epub 2011 Dec 5.
Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis depending upon the genetic background. Utilizing C. rodentium-induced TMCH in C3H/HeNHsd inbred mice, we observed significant crypt hyperplasia on days 3 and 7 preceding active colitis. NF-κB activity in the crypt-denuded lamina propria (CLP) increased within 24 h postinfection, followed by its activation in the crypts at day 3, which peaked by day 7. Increases in interleukin-α1 (IL-1α), IL-12(p40), and macrophage inflammatory protein 1α (MIP-1α) paralleled NF-κB activation, while increases in IL-1α/β, IL-6/IL-12(p40)/granulocyte colony-stimulating factor (G-CSF)/keratinocyte-derived chemokine (KC)/monocyte chemotactic protein 1 (MCP-1), and MIP-1α followed NF-κB activation leading to significant recruitment of neutrophils to the colonic mucosa and increased colonic myeloperoxidase (MPO) activity. Phosphorylation of the crypt cellular and nuclear p65 subunit at serines 276 and 536 led to functional NF-κB activation that facilitated expression of its downstream target, CXCL-1/KC, during TMCH. Distinct compartmentalization of phosphorylated extracellular signal-regulated kinase 1 and 2 ([ERK1/2] Thr(180)/Tyr(182)) and p38 (Thr(202)/Tyr(204)) in the CLP preceded increases in the crypts. Inhibition of ERK1/2 and p38 suppressed NF-κB activity in both crypts and the CLP. Dietary administration of 6% pectin or 4% curcumin in C. rodentium-infected mice also inhibited NF-κB activity and blocked CD3, F4/80, IL-1α/β, G-CSF/MCP-1/KC, and MPO activity in the CLP while not affecting NF-κB activity in the crypts. Thus, distinct compartmentalization of NF-κB activity in the crypts and the CLP regulates crypt hyperplasia and/or colitis, and dietary intervention may be a novel strategy to modulate NF-κB-dependent protective immunity to facilitate crypt regeneration following C. rodentium-induced pathogenesis.
柠檬酸杆菌诱导可传播的鼠结肠增生（TMCH），并根据遗传背景引起不同程度的炎症和坏死。在 C3H/HeNHsd 近交系小鼠中利用柠檬酸杆菌诱导的 TMCH，我们观察到在活性结肠炎前的第 3 天和第 7 天，隐窝出现明显的增生。感染后 24 小时内，CLP 中的 NF-κB 活性增加，随后在第 3 天在隐窝中激活，第 7 天达到峰值。白细胞介素-α1（IL-1α）、IL-12(p40)和巨噬细胞炎症蛋白 1α（MIP-1α）的增加与 NF-κB 激活平行，而 IL-1α/β、IL-6/IL-12(p40)/粒细胞集落刺激因子（G-CSF）/角质形成细胞衍生的趋化因子（KC）/单核细胞趋化蛋白 1（MCP-1）和 MIP-1α 的增加则跟随 NF-κB 激活，导致中性粒细胞大量募集到结肠黏膜，并增加结肠髓过氧化物酶（MPO）活性。磷酸化的隐窝细胞和核 p65 亚基丝氨酸 276 和 536 导致功能性 NF-κB 激活，在 TMCH 期间促进其下游靶标 CXCL-1/KC 的表达。CLP 中磷酸化的细胞外信号调节激酶 1 和 2 ([ERK1/2] Thr(180)/Tyr(182))和 p38 (Thr(202)/Tyr(204))的独特区室化先于隐窝中的增加。ERK1/2 和 p38 的抑制抑制了隐窝和 CLP 中的 NF-κB 活性。在感染柠檬酸杆菌的小鼠中给予 6%果胶或 4%姜黄素的饮食也抑制了 NF-κB 活性，并阻断了 CLP 中的 CD3、F4/80、IL-1α/β、G-CSF/MCP-1/KC 和 MPO 活性，而不影响隐窝中的 NF-κB 活性。因此，隐窝和 CLP 中 NF-κB 活性的独特区室化调节隐窝增生和/或结肠炎，饮食干预可能是一种调节 NF-κB 依赖性保护性免疫以促进柠檬酸杆菌诱导的发病机制后隐窝再生的新策略。
