Human umbilical cord-derived mesenchymal stem cells utilize activin-A to suppress interferon-γ production by natural killer cells
Human umbilical cord-derived mesenchymal stem cells utilize activin-A to suppress interferon-γ production by natural killer cells
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DOI：
10.3389/fimmu.2014.00662
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发表时间：
2014-12-29
影响因子：
7.3
通讯作者：
Jacobs, Roland
中科院分区：
文献类型：
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作者：
Chatterjee, Debanjana;Marquardt, Nicole;Jacobs, Roland
异基因造血干细胞移植(HSCT)后，受者体内的干扰素-γ水平会强烈影响临床结果。人脐带间充质干细胞(UC-MSCs)在造血干细胞移植环境中作为生物耐受诱导剂是很有价值的。因此，我们研究了UC-MSCs影响自然杀伤细胞(NK细胞)介导的干扰素-γ产生的分子机制。同种异体NK细胞与UC-MSCs或间充质干细胞(MSC)培养上清(MSC条件培养液)直接接触培养。我们发现UC-MSCs分泌的可溶性因子通过降低STAT4、NF-KB的磷酸化和T-bet活性而强烈抑制IL-12/11、18诱导的NK细胞产生干扰素-γ。UC-MSCs分泌大量激活素-A，可抑制NK细胞产生干扰素-γ。激活素-A在MSC条件培养液中的中和显著取消了它们的抑制能力。迄今为止，已有多个研究小组报道，MSCs产生的前列腺素(PG)-E_2能抑制NK细胞的功能。事实上，我们发现，抑制骨髓间充质干细胞产生PG E2也可以显著恢复干扰素-γ的产生。然而，激活素-A和前列腺素E_2的作用不是累积的。据我们所知，我们首次报道了激活素-A在MSC介导的NK细胞抑制干扰素-γ产生中的作用。
Following allogeneic hematopoietic stem cell transplantation (HSCT), interferon (IFN)-gamma levels in the recipient's body can strongly influence the clinical outcome. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are lucrative as biological tolerance-inducers in HSCT settings. Hence, we studied the molecular mechanism of how UC-MSCs influence natural killer (NK) cell-mediated IFN-gamma production. Allogeneic NK cells were cultured in direct contact with UC-MSCs or cell-free supernatants from mesenchymal stem cell (MSC) cultures (MSC-conditioned media). We found that soluble factors secreted by UC-MSCs strongly suppressed interleukin (IL)-12/11,18-induced IFN-gamma production by NK cells by reducing phosphorylation of STAT4, NF-KB, as well as T-bet activity. UC-MSCs secreted considerable amounts of activin-A, which could suppress IFN-gamma production by NK cells. Neutralization of activin-A in MSC-conditioned media significantly abrogated their suppressive abilities. Till date, multiple groups have reported that prostaglandin (PG)-E2 produced by MSCs can suppress NK cell functions. Indeed, we found that inhibition of PG E2 production by MSCs could also significantly restore IFN-gamma production. However, the effects of activin-A and PGE2 were not cumulative. To the best of our knowledge, we are first to report the role of activin-A in MSC-mediated suppression of IFN-gamma production by NK cells.