Activin A functions as a Th2 cytokine in the promotion of the alternative activation of macrophages
Activin A functions as a Th2 cytokine in the promotion of the alternative activation of macrophages
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DOI：
10.4049/jimmunol.177.10.6787
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Tsujimoto, Masafumi
中科院分区：
文献类型：
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作者：
Gawa, Kenji;Funaba, Masayuki;Tsujimoto, Masafumi
激活素A是转化生长因子-β超家族成员之一，是一种多能生长分化因子。在这项研究中，我们报告了小鼠Th细胞在激活时产生激活素A。用抗CD3交联剂诱导培养的CD4(+)T细胞的激活素活性。激活后激活素βA的mRNA水平升高，表明CD4(+)T细胞激活素的产生是在mRNA水平上调节的。激活素的产生仅在CD4(+)CD25(-)T细胞中检测到，但在CD4(+)CD25(+)调节性T细胞中未检测到。当CD4(+)T细胞分化为Th细胞亚群时，在Th2偏斜条件下培养可检测到较高的激活素分泌。激活素βA在Th2细胞中表达丰富，而在Th1细胞中不表达。此外，激活的Th2克隆的激活素分泌显著高于Th1克隆。激活素βA近端的启动子包含一个与Th2特异性转录因子c-Maf的结合部位，该部位与一个核因子-AT结合部位非常接近。C-Maf能与核因子-AT协同反式激活激活素βA基因，两种因子均参与Th2细胞中激活素βA的转录。激活素A诱导巨噬细胞表达精氨酸酶-1(M-2表型)，而抑制干扰素-γ诱导的诱导型一氧化氮合酶(M-1表型)表达。综上所述，这些观察表明激活素A是一种新的Th2细胞因子，促进巨噬细胞向M-2表型分化。
Activin A, a member of the TGF-beta superfamily, is a pluripotent growth and differentiation factor. In this study, we report that murine Th cells produce activin A upon activation. Activin activity in the cultured CD4(+) T cells was induced by anti-CD3 cross-linking. Activin beta A mRNA level was increased in response to activation, indicating that activin production in CD4(+) T cells is regulated at the mRNA level. Activin production was detected exclusively in CD4(+)CD25(-) T cells, but not in CD4(+)CD25(+) regulatory T cells. When CD4(+) T cells were differentiated into Th cell subsets, higher activin secretion was detected when cultured under Th2-skewing conditions. The mRNA level of activin beta A was abundant in Th2, but not in Th1 cells. Furthermore, secretion of activin was significantly higher in activated Th2 clones than in Th1 clones. The activin beta A-proximal promoter contains a binding site for c-Maf, a Th2-specific transcriptional factor, at close proximity with an NF-AT binding site. c-Maf was able to synergize with NF-AT to transactivate activin beta A gene, and both factors are implicated in activin beta A transcription in Th2 cells. Activin A induced macrophages to express arginase-1 (M-2 phenotype), whereas it inhibited inducible NO synthase expression (M-1 phenotype) induced by IFN-gamma. Taken together, these observations suggest that activin A is a novel Th2 cytokine that promotes differentiation of macrophages toward the M-2 phenotype.