IL-6在炎症性肠病大鼠脑、结肠组织中表达及信号转导机制研究
摘要
炎症性肠病(IBD)是一种在我国及欧美等诸多国家极为普遍的并且病因未明的慢性胃肠道疾病,与遗传、免疫、环境及黏膜屏障等影响因素密切相关,其中IL-6被认定是与IBD密切相关的核心细胞因子之一。本实验从神经-内分泌-免疫网络的角度出发,运用三硝基苯磺酸(TNBS)化学诱导,按每只大鼠0.2 mL／100 g的剂量进行直肠灌注,建立了IBD大鼠动物模型,并于建模后第0、3、7、14、21、28天取脑、结肠组织和血液。采用免疫组织化学和实时荧光定量方法检测IL-6在结肠和脑组织中的表达变化；采用实时荧光定量的方法检测IL-6受体及其相关信号转导因子(如stat3, jak3, gp130, socs3)在结肠和脑中的变化规律；采用ELISA方法检测血清中IL-6在不同时期的浓度变化。实验结果表明,结肠、脑组织中IL-6、IL-6受体及其相关信号转导因子的表达水平随着炎症性肠病的加重而增加,随着炎症性肠病的恢复而逐渐减少,最后趋向于正常大鼠水平；ELISA实验的结果表明,血清中IL-6的浓度也具有相同的变化趋势。上述结果表明IL-6及其信号转导相关因子与IBD的发生发展存在必然的联系,IL-6及其信号转导相关因子可作为治疗IBD的靶点。本研究的结果为进一步深入研究IBD的发病机制提供了实验依据。同时还为从神经-内分泌-免疫调节网络的角度研究IBD的发病机制奠定了基础。
Nervous-endocrine-immune form a complex network-neuroendocrine-immune regulation network, which controls the body's various life activities, maintain homeostasis of the body. When the homeostasis is disrupted, certain parts in the network will respond and do some change in the function, meanwhile, related link in the network show some change, leading to Certain diseases and the emergence of pathological process. Neuroendocrine and immune disorders are a common feature of all diseases. All the clinical diseases have a nerve-endocrine-immune disorder. The disease process is actually a kind of disorder of nerve-endocrine-immune network homeostasis adjustment. however, among the nerve, endocrine and immune disorders, immune disorder is principal.
Inflammatory bowel disease (IBD) is a universal chronic inflammatory disease, including chronic nonspecific ulcerative colitis (UC) and Crohn's disease (CD), The disease's distribution of is world-wide, and it seriously endangers the health of our people, and the incidence rate is increasing recently. and especially serious in Chinese, Europe and America. The key features of IBD were inflammation of intestinal tract and mucous membrane lesions. The etiology and pathogenesis of IBD are not very clear yet. The majority of researches suggest that IBD is a kind of autoimmune disease caused by the interaction of many factors including heredity, immune, environment and mucosal barrier. Among all of these, immunity plays a vital role in the occurrence and development of IBD. Many research data show that IL-6 is key factor referring to a variety of cytokines during IBD progress.
In view of the above, IBD rats model was constructed by chemical induction of trinitro-benzene-sulfonic acid (TNBS). Briefly,5%TNBS and dehydrated alcohol was mixed referring to 2:1 ratio. The rats were then rectum perfused with the mixture. The rat model was sacrificed on day 3,7,14,21 and 28, and the brain and the colon tissues were stripped. The expression of IL-6 in the brain and the colon tissues was determined by immunohistochemistry and real time PCR. The regulation mechanism of the acceptor and the signal transduction factors, such as stat3, jak3, gp130, socs3, of IL-6 was identified by real time PCR. The concentration diversity of IL-6 in the serum during the treatment period was measured by ELISA. The results showed that the amount of IL-6 and its acceptors and related signal transduction factors in the intestinal change in the pathogenesis of IBD. With the development of IBD, there is a higher expression level of IL-6 and its acceptors and related signal transduction factors. When rats recovered, the expression of IL-6 and its acceptors and related signal transduction factors decreased gradually, and finally reach the normal level. The results of brain tissues were similar to the results of gut. The ELISA experiments indicated that serum IL-6 concentration heightened when have IBD, on the contrary, the serum IL-6 concentration degraded gradually accompany with disease recovery and return to the normal concentration eventually.
In summary, IL-6 was the key factor in chronic phase of colonitis and its acceptors and related signals transduction factors were all involved in the development of IBD, which proved the important role of signal transduction pathway of IL-6 in the morbidity progress of IBD. The study provided the basic theory of pathogenesis research of IBD. The results also prompted that network-neuroendocrine-immune regulation network participated in the progress of IBD, which supplied the relationship research of IBD and network-neuroendocrine-immune regulation network with experimental data.
Nervous-endocrine-immune form a complex network-neuroendocrine-immune regulation network, which controls the body's various life activities, maintain homeostasis of the body. When the homeostasis is disrupted, certain parts in the network will respond and do some change in the function, meanwhile, related link in the network show some change, leading to Certain diseases and the emergence of pathological process. Neuroendocrine and immune disorders are a common feature of all diseases. All the clinical diseases have a nerve-endocrine-immune disorder. The disease process is actually a kind of disorder of nerve-endocrine-immune network homeostasis adjustment. however, among the nerve, endocrine and immune disorders, immune disorder is principal.
Inflammatory bowel disease (IBD) is a universal chronic inflammatory disease, including chronic nonspecific ulcerative colitis (UC) and Crohn's disease (CD), The disease's distribution of is world-wide, and it seriously endangers the health of our people, and the incidence rate is increasing recently. and especially serious in Chinese, Europe and America. The key features of IBD were inflammation of intestinal tract and mucous membrane lesions. The etiology and pathogenesis of IBD are not very clear yet. The majority of researches suggest that IBD is a kind of autoimmune disease caused by the interaction of many factors including heredity, immune, environment and mucosal barrier. Among all of these, immunity plays a vital role in the occurrence and development of IBD. Many research data show that IL-6 is key factor referring to a variety of cytokines during IBD progress.
In view of the above, IBD rats model was constructed by chemical induction of trinitro-benzene-sulfonic acid (TNBS). Briefly,5%TNBS and dehydrated alcohol was mixed referring to 2:1 ratio. The rats were then rectum perfused with the mixture. The rat model was sacrificed on day 3,7,14,21 and 28, and the brain and the colon tissues were stripped. The expression of IL-6 in the brain and the colon tissues was determined by immunohistochemistry and real time PCR. The regulation mechanism of the acceptor and the signal transduction factors, such as stat3, jak3, gp130, socs3, of IL-6 was identified by real time PCR. The concentration diversity of IL-6 in the serum during the treatment period was measured by ELISA. The results showed that the amount of IL-6 and its acceptors and related signal transduction factors in the intestinal change in the pathogenesis of IBD. With the development of IBD, there is a higher expression level of IL-6 and its acceptors and related signal transduction factors. When rats recovered, the expression of IL-6 and its acceptors and related signal transduction factors decreased gradually, and finally reach the normal level. The results of brain tissues were similar to the results of gut. The ELISA experiments indicated that serum IL-6 concentration heightened when have IBD, on the contrary, the serum IL-6 concentration degraded gradually accompany with disease recovery and return to the normal concentration eventually.
In summary, IL-6 was the key factor in chronic phase of colonitis and its acceptors and related signals transduction factors were all involved in the development of IBD, which proved the important role of signal transduction pathway of IL-6 in the morbidity progress of IBD. The study provided the basic theory of pathogenesis research of IBD. The results also prompted that network-neuroendocrine-immune regulation network participated in the progress of IBD, which supplied the relationship research of IBD and network-neuroendocrine-immune regulation network with experimental data.
引文
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