Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation.
Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation.
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DOI：
10.1097/mib.0000000000000297
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发表时间：
2015-03
影响因子：
4.9
通讯作者：
Scharl M
中科院分区：
文献类型：
--
作者：
Spalinger MR;McCole DF;Rogler G;Scharl M
目前的假说表明，遗传、免疫和细菌因素对炎症性肠病（IBD）的发病机制有重要作用。编码蛋白酪氨酸磷酸酶（PTPs）的基因位点的变异与IBD的发病有关。PTPs通过对酪氨酸残基进行去磷酸化来调节其底物的活性，对基本的细胞信号传导过程的调节至关重要。有证据表明，在炎症活跃的肠道组织中，PTPN2、PTPN11和PTPN22的表达水平发生了改变。PTPN2似乎对保护肠道上皮屏障功能、调节先天性和适应性免疫反应以及最终维持肠道内稳态至关重要。这些观察结果已在体内PTPN2基因敲除小鼠中得到证实。这些动物明显更易患肠道和全身性炎症，并且先天性和适应性免疫反应发生改变。PTPN22控制淋巴细胞和单核细胞中的炎症信号传导，导致细胞因子分泌模式异常和自噬体形成。体内PTPN22缺乏会导致更严重的结肠炎，这表明PTPN22对体内肠道内稳态的相关性。值得注意的是，PTPN22的缺失促进丝裂原活化蛋白激酶（MAPK）诱导的细胞因子分泌，但限制单核细胞中核因子κB（NFκB）相关细胞因子的分泌和自噬。PTPN11的缺失在体内也与结肠炎严重程度增加有关。总之，这些PTPs的功能障碍导致异常且不受控制的免疫反应，从而引发慢性炎症疾病。这样，越来越明显的是，PTPs的功能障碍是慢性肠道炎症，特别是IBD发病机制中的一个重要因素。
Current hypothesis suggests that genetic, immunological and bacterial factors contribute essentially to the pathogenesis of inflammatory bowel disease (IBD). Variations within the gene loci encoding protein tyrosine phosphatases (PTPs) have been associated with the onset of IBD. PTPs modulate the activity of their substrates by dephosphorylation of tyrosine residues and are critical for the regulation of fundamental cellular signalling processes.Evidence emerges that expression levels of PTPN2, PTPN11 and PTPN22 are altered in actively inflamed intestinal tissue. PTPN2 seems to be critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses and finally for maintaining intestinal homeostasis. These observations have been confirmed in PTPN2 knock-out mice in vivo. Those animals are clearly more susceptible to intestinal and systemic inflammation and feature alterations in innate and adaptive immune responses. PTPN22 controls inflammatory signalling in lymphocytes and mononuclear cells resulting in aberrant cytokine secretion pattern and autophagosome formation. PTPN22-deficiency in vivo results in more severe colitis demonstrating the relevance of PTPN22 for intestinal homeostasis in vivo. Of note, loss of PTPN22 promotes MAPK-induced cytokine secretion, but limits secretion of NFκB-associated cytokines and autophagy in mononuclear cells. Loss of PTPN11 is also associated with increased colitis severity in vivo. In summary, dysfunction of those PTPs results in aberrant and uncontrolled immune responses that result in chronic inflammatory conditions. This way, it becomes more and more evident that dysfunction of PTPs displays an important factor in the pathogenesis of chronic intestinal inflammation, in particular IBD.