Zcchc6在TLR4訊息傳遞中扮演的角色

先天性免疫系統經由pattern-recognition receptors (PRRs)來辨識微生物，並且抵抗微生物感染，然而，過量的cytokines會導致過度的發炎反應，進一步促使發炎相關的併發症；但是cytokines不足，又不能引發足夠的免疾反應，抵抗微生物感染。因此，cytokines的量必須受到嚴密的調控。Toll-like Receptors(TLRs)為PRRs其中一類重要的家族。在lipopolysaccharide (LPS)的刺激之下，活化TLR4，並經由一系列的訊息傳遞，導致增加cytokines、chemokines以及type I interferon的表現量。這些cytokines可以幫助抵抗微生物的感染、協助傷口癒合，以及引發後天性免疫反應。大約有2%的基因會受到LPS的刺激而增加，有些基因已經清楚的被研究，像是cytokines和chemokines，但大部份受到LPS誘導的基因，其生理性上的功能尚未清楚。我們搜尋National Center for Biotechnology Information (NCBI)的Gene Expression Omnibus (GEO)資料庫，並進一步的分析可被LPS誘導並提升表現量的基因，找出了包含zinc-finger domain的Zcchc6。Zcchc6屬於TUTase family，擁有poly(U) polymerase (PUP) 或者是 terminal uridyl transferase (TUTase)的活性。TUTase family的成員已知能夠對small RNAs或mRNA進行末端加U或A，藉此調控RNA的穩定性。我們的研究結果顯示，在bone marrow derived macrophage (BMDMs) 以及 RAW264.7 巨噬細胞中，經由LPS刺激之後， Zcchc6的表現量會提升。我們也發現了Zcchc6具有調控LPS所誘導基因的功能，而這些基因都是受到p38調控的基因。我們進一步的探討了Zcchc6調控IL-6的機制，IL-6是一個pro-inflammatory的cytokine，會參與許多的生理和疾病的調控。IL-6在Zcchc6 knockdown的細胞中，會有較短的mRNA半衰期。而進一步的研究發現，Zcchc6會經由IL-6 3’-UTR的第56到104個核苷酸區堿來調控IL-6的穩定性。綜合以上結果，我們的研究證實Zcchc6對於調控TLR4媒介的免疫反應中，扮演著重要的角色。

關鍵字

先天性免疫； Zcchc6 ； Toll-like receptor 4 ； TLR4

並列摘要

The innate immune cells recognizes microorganism via pattern-recognition receptors (PRRs) to defend the host from infection. However, too much cytokine induction causes an excessive inflammatory response, which contributes to the pathogenesis of chronic inflammatory and infectious diseases, whereas insufficient cytokine production leads to insufficient defense against pathogens and infections. Thus, the tight control of innate immune response is of great importance. Toll-like Receptors (TLRs), a family of PRRs, are key components in the innate immune response. Upon lipopolysaccharide (LPS) stimulation, TLR4 recruits downstream adaptor molecules to activate mitogen-activated protein kinases (MAPKs) and IKK/NF-kB leading to the upregulation of pro-inflammatory cytokines, chemokines and type I interferons. These are important to fight infectious pathogens and wound healing. Approximately 2% of mammalian genes are induced in immune cells after stimulation with LPS. Although some of them are well-recognized, such as cytokines and chemokines, the biological functions of most of LPS-induced genes remain largely unknown. We recently searched the microarray datasets from Gene Expression Omnibus on National Center for Biotechnology Information (NCBI), and found a zinc-finger containing protein, Zcchc6, which was induced upon LPS treatment. ZCCHC6 belongs to a subgroup of DNA polymerase b-like family- possessing either poly(U) polymerase (PUP) and/or terminal uridyltransferase (TUTase) activity. This subfamily (TUTase) has been shown to possess the ability to uridylate or adenylate small RNAs and/or mRNAs, thereby regulating the stability of the target RNA. We verified the elevated expression of Zcchc6 in LPS-induced bone marrow derived macrophage (BMDMs) and RAW264.7 macrophages. We also found that Zcchc6 plays an important role in regulating the expression of several LPS-induced genes in a p38-dependent manner. We further studied the underlying mechanism by which Zcchc6 regulates IL-6, a pro-inflammatory cytokine involved in multiple biological processes and diseases. We demonstrated that Zcchc6 modulated IL-6 mRNA stability via its 3’-UTR56-104 region. Taken together, our findings strongly indicate that Zcchc6 plays a crucial role in the regulation of TLR4-mediated immune response.

並列關鍵字

innate immunity ； Zcchc6 ； Toll-like receptor 4 ； TLR4

參考文獻

Aggarwal, B. B., S. Shishodia, et al. (2006). "Inflammation and cancer: how hot is the link?" Biochem Pharmacol 72(11): 1605-1621.

Akira, S. and K. Takeda (2004). "Toll-like receptor signalling." Nat Rev Immunol 4(7): 499-511.

Akira, S., S. Uematsu, et al. (2006). "Pathogen recognition and innate immunity." Cell 124(4): 783-801.

Anders, H. J., V. Vielhauer, et al. (2003). "Chemokines and chemokine receptors are involved in the resolution or progression of renal disease." Kidney Int 63(2): 401-415.

Anderson, P. (2008). "Post-transcriptional control of cytokine production." Nat Immunol 9(4): 353-359.

國際替代計量

Zcchc6在TLR4訊息傳遞中扮演的角色

全文下載

主題瀏覽