Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease.
Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease.
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DOI：
10.1053/j.gastro.2010.01.005
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发表时间：
2010-04
期刊：
影响因子：
29.4
通讯作者：
Han J
中科院分区：
文献类型：
--
作者：
Otsuka M;Kang YJ;Ren J;Jiang H;Wang Y;Omata M;Han J
p38α是一种介导炎症反应的丝裂原活化蛋白激酶，但其在炎症性肠病（IBD）中的作用尚不清楚。在IBD动物模型和临床研究中，p38α抑制剂的作用不一致，这可能与p38α在不同组织或细胞类型中的功能不同有关。我们研究了p38α抑制在髓样与结肠上皮中的作用。我们研究了骨髓细胞特异性和肠上皮细胞特异性破坏p38α的小鼠（LtrLysCre-p38αΔ/Δ小鼠和VillinCre-p38αΔ/Δ小鼠），以及p38β、γ和δ敲除小鼠。使用葡聚糖硫酸钠（DSS）或2.4.6-三硝基苯磺酸（TNBS）诱导结肠炎。与野生型小鼠相比，髓样细胞特异性p38α缺失的小鼠炎症较少，疾病状况改善，而肠上皮细胞特异性p38α缺失的小鼠结肠炎进展加快，这是由于肠上皮稳态破坏所致。p38α破坏在不同组织类型中的不同作用可能是p38抑制剂在结肠炎治疗应用中不成功的基础。我们发现，γ-分泌酶抑制剂在调节肠上皮稳态中的作用与p38抑制剂相反，可以显著改善p38抑制剂在减轻结肠炎中的作用。p38α在小鼠骨髓细胞和结肠上皮细胞中具有不同的功能;在确定p38α在炎症中的作用和开发p38抑制剂作为治疗药物时应考虑这些差异。
p38α is a mitogen-activated protein kinase that mediates inflammatory responses, but its role in inflammatory bowel disease (IBD) is unclear. The effects of p38α inhibitors have been inconsisten in animal models and clinical studies of IBD, possibly arising from the different functions of p38α in different tissues or cell types. We investigated the effects of p38α inhibition in myeloid vs. the colonic epithelium. We studied mice with myeloid cell-specific and intestinal epithelial cell-specific disruption p38α (LtrLysCre-p38αΔ/Δ mice and VillinCre-p38αΔ/Δ mice), as well as p38β, γ, and δ knockout. Colitis was induced using Dextran Sodium Sulfate (DSS) or 2.4.6-trinitrobenzene sulfonic acid (TNBS). Mice with myeloid cell-specific deletion of p38α had less inflammation and an improved disease condition, compared with wild-type mice, whereas mice with intestinal epithelial cell-specific deletion of p38α had increased progression of colitis that resulted from disrupted intestinal epithelial homeostasis. The distinct effects of p38α disruption in different tissue types might underlie the unsuccessful therapeutic application of p38 inhibitors to colitis. We found that a γ-secretase inhibitor, which functions opposite that of a p38 inhibitor in the regulation of intestinal epithelial homeostasis, can significantly improve the effects of a p38 inhibitor in reducing colitis. p38α has distinct functions in mouse myeloid cells vs. colonic epithelium; these differences should be taken into consideration in defining the role of p38α in inflammation and developing p38 inhibitors as therapeutics.
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