本文選題：Sertoli細胞 + TLR信號通路��； 參考：《中國協(xié)和醫(yī)科大學》2010年博士論文

【摘要】： TAM為受體酪氨酸激酶的一個亞家族,由三個成員組成,即Tyro 3, Axl和Mer,簡稱為TAM受體。Toll-like受體(Toll like receptors, TLRs)是一種模式識別受體,識別病原微生物進化中的保守分子。TLRs在介導天然免疫和獲得性免疫中發(fā)揮著重要的作用。在機體內,外來的病原體能夠激活TLRs誘導產生大量的炎癥因子,這些炎癥因子可以殺傷入侵的病原體。然而TLRs持續(xù)活化會形成慢性炎癥環(huán)境,對機體產生破壞作用,因此TLR信號通路的激活必須受到嚴格的調控。在睪丸組織中,作為唯一與生精細胞相接觸的細胞,Sertoli細胞表達較高水平的TLR3受體,它的活化可以誘導炎癥因子的表達,進而對外侵病原體產生免疫防御作用。為防止睪丸組織持續(xù)產生慢性炎癥反應,Sertoli細胞中TLR3受體的活化必須受到嚴格的調控。本實驗研究了TAM受體負調控Sertoli細胞TLR3信號的作用與機理。 結果發(fā)現(xiàn),Sertoli細胞中同時表達Tyro3, Axl和Mer受體。敲除TAM三個受體的Sertoli細胞在受到Poly(I:C) (TLR3的特異性配體)刺激時,TLR3處于超激活狀態(tài),炎癥因子(IL-1β, IL-6和TNFα)和Ⅰ型干擾素(IFNa及IFNβ)表達明顯增多。Sertoli細胞中的TLR3激活后,會引起核因子κB(NF-κB)和干擾素調節(jié)因子3(IRF3)的活化,進而誘導該細胞分泌炎癥因子(IL-1β, IL-6和TNFa)和Ⅰ型干擾素(IFNa及IFNβ)。Gas6是TAM受體的特異性配體,在正常Sertoli細胞中加入Gas6能夠顯著抑制Poly(I:C)誘導的炎癥因子表達,而敲除TAM受體的Sertoli細胞中Gas6不能發(fā)揮這種抑制作用。深入研究發(fā)現(xiàn),TAM激活后促使信號轉導和轉錄活化因子1(STAT1)表達,STAT1又促進TLRs負調控因子——細胞因子信號抑制物1(SOCS1)和3(SOCS3)表達,SOCS1/3抑制TLR3信號通路。這些結果表明,Sertoli細胞中TAM受體參與了負調控TLR3信號通路,其機制是通過上調TLRs負調控因子表達水平實現(xiàn)的。進一步我們發(fā)現(xiàn)這一調控系統(tǒng)在體內具有重要的生理意義。 本研究闡明了TAM受體負調控Sertoli細胞中TLR3的作用機理。它可以防止生精上皮對外來及自身抗原的過度免疫反應,在維持睪丸的免疫穩(wěn)態(tài)中發(fā)揮著重要作用。
[Abstract]:Tam is a subfamily of receptor tyrosine kinase, which consists of three members: Tyro 3, Axl and Mer.TLRs are pattern recognition receptors. TLRs, a conserved molecule in the evolution of pathogenic microorganisms, play an important role in mediating innate and acquired immunity. In the body, foreign pathogens can activate TLRs to induce the production of a large number of inflammatory factors, which can kill the invading pathogens. However, the continuous activation of TLRs can form chronic inflammatory environment and damage the body, so the activation of TLR signaling pathway must be strictly regulated. In testicular tissue, Sertoli cells, the only cells in contact with spermatogenic cells, express a higher level of TLR3 receptor, its activation can induce the expression of inflammatory factors, and then invade the pathogen to produce immune defense. The activation of TLR3 receptor in Sertoli cells must be strictly regulated in order to prevent the persistent chronic inflammatory reaction in testicular tissue. The effect and mechanism of TLR3 signal regulated by TAM receptor in Sertoli cells were studied. It was found that Tyro3, Axl and Mer receptors were expressed in Sertoli cells. Sertoli cells knockout the three receptors of TAM were stimulated by Poly (I: C) (specific ligand of TLR3). The expression of inflammatory factors (IL-1 尾, IL-6 and TNF 偽) and interferon type I (IFNa and IFN 尾) in Sertoli cells was significantly increased after the activation of TLR3 in Sertoli cells. It causes activation of nuclear factor- 魏 B (NF- 魏 B) and interferon regulatory factor 3 (IRF3), which in turn induces the secretion of inflammatory cytokines (IL-1 尾, IL-6 and TNFa) and interferon type I (IFNa and IFN 尾) .Gas6, which are specific ligands of TAM receptor. Adding Gas6 to normal Sertoli cells could significantly inhibit the expression of inflammatory factors induced by Poly (I: C), but Gas6 could not play such an inhibitory role in Sertoli cells knockout TAM receptor. It was found that after activation of TAM, signal transduction and transcription activator 1 (STAT1) expression and STAT1 and TLRs negative regulatory factor-cytokine signal suppressor 1 (SOCS1) and cytokine signal inhibitor 3 (SOCS3) expression were enhanced. SOCS1 / 3 inhibited TLR3 signaling pathway. These results suggest that TAM receptor participates in the negative regulation of TLR3 signaling pathway in Sertoli cells, and its mechanism is by upregulating the expression of TLRs negative regulatory factors. Further, we found that this regulatory system has important physiological significance in vivo. In this study, the mechanism of TLR3 in Sertoli cells was elucidated by the negative regulation of TAM receptor. It can prevent the excessive immune response of spermatogenic epithelium to foreign and autoantigen, and play an important role in maintaining the immune homeostasis of testis.
【學位授予單位】：中國協(xié)和醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2010
【分類號】：R392

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本文編號：2064670