腫瘤壞死因子第三號誘餌受體之免疫調節作用

Immunomodulatory Effects of Decoy Receptor 3 (DcR3)

腫瘤壞死因子及其受體對調控細胞之增生、分化、凋亡及免疫反應，扮演十分重要的角色，其大多數成員具有穿膜區段並以膜蛋白形式表現在細胞表面上。1998年，一個新的腫瘤壞死因子受體－－第三號誘餌受體－－被發現會在癌細胞中大量表現，由於其缺乏穿膜區段，是以可溶性蛋白的方式存在，並可以中和FasL、LlGHT、TLlA對細胞毒殺及活化T細胞的生物功能。因此以往的研究多認為癌細胞藉分泌第三號誘餌受體來逃避免疫系統的攻擊。可是我們的研究發現，第三號誘餌受體不單是可以中和其配體所造成的生物功能，其本身還可以抑制樹狀細胞和巨噬細胞的正常分化和活化，並促進噬骨細胞的產生，這些現象和癌細胞附近的巨噬細胞不正常形態及功能很像。此外，當癌症病人的癌細胞轉移到骨頭時常會造成骨質疏鬆的現象，所以我們認為第三號誘餌受體很有可能在癌細胞所造成的病變中扮演重要的角色。除此之外，在非肥胖性糖尿病的小鼠動物模型上，第三號誘餌受體也可以延遲糖尿病的發生和增加移植的胰島細胞的存活率，這個動物模型提供了一個第三號誘餌受體在治療自體免疫疾病上可能的應用方式。

Members of the tumor necrosis factor (TNF) family have been shown to play important roles in diverse biological function, such as proliferation, differentiation, cytokine secretion, apoptosis, immunoglobulin class switching and T cell costimulation. Receptors in this family share a common structural motif in their extracellular domains consisting of multiple cysteine-rich repeats of approximately 30-40 amino acids. Most TNF receptors contain a functional cytoplasmic domain to associate with downstream signaling molecules. However, some members of the TNFR superfamily do not have cytoplasmic domains and are expressed as a secreted, protein, such as osteoprotegerin (OPG), or linked to cell membrane through a glycophospholipid tail, such as TRID/DcR1/TRAIL-R3. Decoy receptor 3 (OcR3) was identified in 1998 by searching expressed sequence tag (EST) databases lo find out genes with homology to the tumor necrosis factor (TNF) receptor (TNFR) gene super-family. The open reading frame of DcR3 encodes 300 amino acids with a 29-residue signal sequence and four tandem cysteine-rich repeats that are the hallmark of the TNFR superfamily. Unlike most of the other TNFR family members, no transmembrane domain can be identified, indicating that the DcR3 protein is secreted protein. Moreover, DcR3 is mapped to extreme telomere of chromosome 20 at 20q13.3, a region known to be associated with gene amplification and rearrangement in human cancer. In normal situation, the expression of DcR3 can be detected in fetal brain, lung, liver, adult lung, spleen, colon, stomach, spinal cord, lymph node cytotrophoblasts, amnion, and decidna capsularis Several stimulations have been reported to activate DcR3 expression, such as virus infection, UV irradiation, and endotoxin challenge-induced acute inflammation. DcR3 does not only have neutralizing activities, but also acts as an effector molecule to trigger multiple signaling pathways, including the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and c-Jun NH2-terminal protein kinase (JNK), and the transcription factor NF-KB in intestinal endothelial cells, phosphatidylinositol 3-kinase, and Src-like tyrosine kinase in monocytes and dendritic cells8.