TNF-α透過CD69抑制紅血球基因的表現

TNF-α Inhibits the Expressions of Erythroid Genes Through CD69

劉晉維

貧血 ； TNF-α ； CD69 ； activin A

臺北醫學大學醫學科學研究所學位論文

2013年

碩士

黃惠美

繁體中文

貧血，在慢性發炎以及癌症的病患中是一種普遍的併發症，這些病患體內會伴隨著TNF-α的大量表現。TNF-α可以抑制紅血球分化，但透過何種機制目前仍是未知。本實驗室之前的研究結果顯示，紅血球分化因子activin A，會透過p38 MAPK途徑誘導K562細胞進行紅血球分化，TNF-α能回復activin A對CD69蛋白質的抑制作用，且CD69大量表現會抑制紅血球分化。因此CD69可能參與TNF-α抑制細胞進行紅血球分化的角色。本論文證實TNF-α會抑制activin A對α-globin和ζ-globin的誘導作用。TNF-α會回復activin A 對stem cell marker基因的抑制作用。將p38α knockdown後加入activin A，發現CD69的表現會增加，此研究結果顯示activin A會透過p38α進而使CD69的表現減少。CD69 knockdown後，TNF-α抑制α-globin和ζ-globin的現象會消失，而且TNF-α抑制activin A對α-globin和ζ-globin的誘導作用會回復，此結果表示TNF-α會透過CD69降低activin A對α-globin和ζ-globin的誘導。另外，CD69 knockdown後，TNF-α對紅血球轉錄因子NF-E2p45的抑制情形沒有改變，此結果指出TNF-α透過CD69抑制α-globin和ζ-globin的過程不是藉由抑制NF-E2p45。這些結果證實了activin A誘導紅血球分化的過程中會透過p38α降低CD69的表現，而TNF-α抑制紅血球生成的訊息路徑中，則會透過CD69抑制由activin A所誘導的紅血球分化。

Anemia is a common complication in chronic inflammation and cancer patients. High level of tumor necrosis factor-?? (TNF-??) can be detected within these patients. TNF-?? can inhibit erythroid differentiation, however the mechanism of this inhibition is still unknown. In our previous studies, erythroid differentiation factor (EDF), activin A, can induce erythroid differentiation through p38 MAPK pathway in K562 cells. In addition, TNF-?? can reverse CD69 expression which is inhibited by activin A. On the other hand, CD69 overexpression inhibited erythroid differentiation in K562 cells. These results suggest that CD69 might involve in the inhibition of erythroid differentiation mediated by TNF-??. In this study, TNF-?? supresses activin A-induced ??-globin and ζ-globin expressions, TNF-?? reverses activin A-mediated stem cell marker genes inhibition also being proved. After knocking-down of p38?? and adding of activin A, CD69 expression is up-regulated. This result shows that activin A reduces CD69 expression through p38??. After CD69 knockdown, TNF-?? inhibition of ??-globin and ζ-globin expression is reversed. Besides, TNF-?? inhibition of activin A-induced ??-globin and ζ-globin expression is restored. These results show that TNF-?? decreases activin A-induced ??-globin and ζ-globin expression via CD69. Also, knockdown of CD69 does not affect the expression of erythroid differentiation factor,NF-E2p45, which is inhibited by TNF-??. Thus, inhibition of ??-globin and ζ-globin by CD69 mediated by TNF-?? is not relied on NF-E2p45. In short, activin A reduces CD69 expression via p38?? to induce globin gene expressions. Also, during TNF-?? inhibition of erythropoiesis, CD69 inhibits activin A-induced erythroid differentiation.