多胺抑制類嗜中性白血球之第四型類鐸受體訊息傳遞

Polyamines suppress Toll-like receptor 4 signaling in neutrophil-like cells

陳凱芳(Kai-Fan Chen)

指導教授 ： 廖雅芳

朝陽科技大學/理工學院/應用化學系生化科技碩士班/碩士(2013年)

摘要

嗜中性白血球是第一個到達發炎位置的免疫細胞，而第四型類鐸受體是活化嗜中性白血球的重要調節者。革蘭氏陰性菌的脂多醣為活化第四型類鐸受體的訊息傳導路徑之主要活化者，能夠誘導嗜中性白血球釋放細胞激素，促進發炎反應。多胺在許多生理的功能上扮演著重要的角色，包括細胞週期的調控、細胞的增生與免疫調節，在免疫調節方面，多胺被發現抑制促發炎細胞激素的合成，然而多胺如何調節此種免疫反應的機制仍不清楚。因此，本研究探討多胺是否透過調節第四型類鐸受體的訊息傳遞，進而抑制促發炎細胞激素表現。首先研究發現多胺能夠抑制第四型類鐸受體的mRNA和蛋白質的表現，而且多胺能夠減少脂多醣所刺激的類嗜中性白血球的IL-1b之表現。另一方面，在類嗜中性白血球上處理NF-kB抑制劑BAY-11-7082與AP-1抑制劑Curcumin發現抑制第四型類鐸受體的表現，更進一步以多胺處理發現能減少NF-kB與AP-1的表現。綜合上述結果顯示多胺是經由降低發炎前驅轉錄因子NF-kB和AP-1的表現，進而減少類嗜中性白血球上的第四型類鐸受體之表現，最後導致其訊息傳遞被抑制。

關鍵字

多胺

並列摘要

Neutrophils are the first immune cells to arrive at sites of infection. Bacterial products induce the release of proinflammatory cytokines in neutrophils. Lipopolysaccharide (LPS) is the principal outer membrane component of Gram-negative bacteria that activates Toll-like receptor 4 (TLR4) signaling pathway. TLR4 is one of the most important regulators of neutrophil activation. Polyamines play an important role in many biological functions, including cell cycle, proliferation and immunomodulation. Polyamines specifically suppress the synthesis of proinflammatory cytokines. However, how it regulates the immune responses is still unclear. Therefore, we examined whether polyamines regulated TLR4 signaling to inhibit proinflammatory cytokines . In this study, we found that polyamines inhibited TLR4 protein and mRNA expression. Moreover, polyamines repressed IL-1b expression in neutrophil-like cells to response LPS. In addition, a NF-kB inhibitor BAY-11-7082 and an AP-1 inhibitor curcumin suppressed TLR4 expression in neutrophil-like cells. We further found polyamines inhibited NF-kB and AP-1 expression in neutrophil-like cells. These results demonstrated that polyamines could inhibit TLR4 signaling through repressing proinflammatory transcription factors NF-kB and AP-1 expression in neutrophil-like cells.

並列關鍵字

Polyamines

參考文獻

Adler S, Pellizzer C, Paparella M, Hartung T, Bremer S. 2006. The effects of solvents on embryonic stem cell differentiation. Toxicol In Vitro 20(3):265-271.

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

Breitman TR, Selonick SE, Collins SJ. 1980. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A 77(5):2936-2940.

Choi YH, Park HY. 2012. Anti-inflammatory effects of spermidine in lipopolysaccharide-stimulated BV2 microglial cells. J Biomed Sci 19:31.

Collins SJ, Bodner A, Ting R, Gallo RC. 1980. Induction of morphological and functional differentiation of human promyelocytic leukemia cells (HL-60) by componuds which induce differentiation of murine leukemia cells. Int J Cancer 25(2):213-218.