其他細胞激素對 activin A 誘導紅血球分化之抑制作用及作用機制
Mechanism underlying the inhibition of other cytokines on activin A-mediated erythroid differentiation
中文摘要
紅血球的生成是指造血前驅細胞分化成紅血球的過程，這個過程已被廣泛的研 究。許多實驗已經證實關於造血前驅細胞增生與紅血球分化的過程需要特殊細胞 激素的參與。Activin A 是 TGF- 家族中的一員，Activin A 是多功能性的細胞激 素，參與多種細胞的增生、分化與細胞凋亡。Activin A 也稱為紅血球分化因子 能誘導erythroleukemia 細胞的分化。腫瘤壞死因子 (TNF- )和干擾素 (INF- )於體內或是體外的 hematopoiesis 有重要的影響，且均能抑制 erythropoiesiss。
這些細胞激素間，如何互相調控造血細胞中紅血球的分化並未被報導。本篇論文 中，我們證明TNF- 與 INF- 能在 erythroleukemia K652 細胞中，以濃度依賴 的模式抑制Activin A 誘導人類 球蛋白 promoter 的活性。相對的 Activin A 能夠 以濃度依賴的模式，避免TNF- 抑制人類 球蛋白 reporter 的活性。此外 TNF- 能夠抑制K562 細胞的增生，但不影響 Activin A 所抑制的 K562 細胞增生。
另外，當加入PDTC 抑制 NF- B 路徑時，能回復 TNF- 與 INF- 減少 Activin A 所誘導的 K562 細胞之紅血球系細胞分化；這也暗示 NF- B 在這方面調控的 重要性。相對而言p38 抑制劑，SB203580，不能回復 TNF- 與 INF- 抑制 Activin A 誘導的紅血球分化的能力。TNF- 與 INF- 也會透過NF- B 路徑誘導 c-Jun 的表現。c-Jun 加強 TNF- 抑制紅血球的分化，而 c-Jun dominant negative mutant
回復TNF- 所抑制的紅血球分化。這些實驗結果暗示 TNF- 會透過 NF- B 與
c-Jun 抑制 Activin A 對紅血球生成的影響；而 INF- 也會透過 NF- B 抑制 Activin A 對紅血球生成的影響。
英文摘要
Erythropoiesis, the development of hematopoietic progenitor cells to more differentiated red blood cells, has been studied extensively in vitro. It has been demonstrated that the in vitro proliferation of erythroid progenitor cells and its differentiation into erythrocytes are dependent on the presence of specific cytokines.
Activin A, a member of the transforming growth factor (TGF)- superfamily, is a multifunctional cytokine that regulates cell proliferation, differentiation, and apoptosis in various cell types. Activin A, also termed the erythroid differentiation factor,
induces the differentiation of erythroleukemia cells. Tumor necrosis factor- (TNF- ) and interferon- (INF- ) have significant effects on hematopoiesis in vitro and in vivo. Both cytokineshave been shown to inhibit erythropoiesis. How these
cytokines interact together to affect the regulation of erythroid differentiation in
hematopoietic cells have not been elucidated. In this study, we demonstrated that TNF- and INF- reduced activin A-induced -globin gene promoter activity in the erythroleukemia cell line K562 in a dose dependent manner. On the other hand, activin A prevented TNF- -induced suppression of erythroid differentiation in a dose dependent manner. In addition, TNF- inhibited cell proliferation. However, TNF- did not affect activin A-mediated growth inhibition of K562 cells. The addition of PDTC to inhibit NF- B resulted in reversing the effect of TNF- and INF- to reduce activin A-mediated erythroid differentiation, indicating that NF- B signaling is crucial for this regulation. In contrast, the p38 inhibitor, SB203580, did not
overcome the inhibitory effect of TNF- and INF- on activin A-mediated erythroid differentiation. TNF- and INF- also induced c-Jun expression through the NF- B pathway. c-Jun enhanced the inhibitory effect of TNF- on erythroid differentiation, whereas c-Jun dominant negative mutant reversed this inhibitory effect of TNF- . These results suggested that TNF- reduced the effects of activin A on
erythropoiesis via the NF- B pathway and c-Jun; INF- also reduced the effects of activin A on erythropoiesis via the NF- B pathway.
