Concentration-dependent bifunctional effect of TGF-β1 on immunoglobulin production:: a role for Smad3 in IgA production in vitro
Concentration-dependent bifunctional effect of TGF-β1 on immunoglobulin production:: a role for Smad3 in IgA production in vitro
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DOI：
10.1016/j.intimp.2003.08.001
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发表时间：
2003-12-01
影响因子：
5.6
通讯作者：
Kaminski, NE
中科院分区：
文献类型：
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作者：
McKarns, SC;Letterio, JJ;Kaminski, NE
肝脏损伤导致转化生长因子β 1（TGF-β 1）的快速诱导，这与TGF-β 1在修复受损组织中的作用一致。除了其在损伤修复中的普遍作用外，TGF-β（1）也被公认为免疫稳态的关键调节剂;然而，其作用机制仍然是谜。我们以前已经证明，肝毒性氯化烃，四氯化碳，抑制辅助T淋巴细胞功能的TGF-β（1）依赖的方式。在这里，我们报告说，与皮摩尔浓度的免疫抑制作用相反，飞摩尔浓度的TGF-β（1）增强T细胞依赖性抗sRBC IgM抗体形成细胞（AFC）和T细胞非依赖性DNP-Ficoll诱导的AFC反应。这些数据支持TGF-β（1）对体外体液免疫应答的浓度依赖性双功能效应。我们进一步研究了Smad 3（TGF-β（1）信号转导的细胞内介质）在传播TGF-β（1）对体液免疫应答的抑制作用中的假定机制作用。与野生型同窝出生小鼠相比，与编码TGF-β受体激活的Smad 3（Smad 3（Exon 8-/-））的基因中的无效突变同源的小鼠脾细胞在体外抗sRBC和LPS致敏后对TGF-β（1）抑制的敏感性较低。与此一致，TGF-β 1对IgM蛋白产生的抑制作用在LPS致敏的Smad 3（外显子8-/-）脾B细胞中也受到抑制。此外，在LPS致敏的Smad 3（外显子8-/-）脾细胞中，TGF-β（1）对伊加的刺激被消除，这表明Smad 3在体外调节伊加产生中具有额外的作用。我们的研究结果表明，TGF-β（1）对体液免疫反应的影响在浓度依赖性方面存在根本性差异，并且部分通过Smad 3信号转导介导。(C)2003 Elsevier B. V.保留所有权利。
Injury to the liver results in rapid induction of transforming growth factor-betal (TGF-beta(1)) consistent with a role for TGF-beta(1) in repairing damaged tissue. In addition to its ubiquitous role in injury repair, TGF-beta(1) is also well established as a critical regulator of immune homeostasis; however, its mechanisms of action remain enigmatic. We have previously demonstrated that the hepatotoxic chlorinated hydrocarbon, carbon tetrachloride, suppresses helper T-lymphocyte function in a TGF-beta(1)-dependent manner. Here, we report that, in opposition to its immunosuppressive effects at picomolar concentrations, femtomolar concentrations of TGF-beta(1) augment T cell-dependent anti-sRBC IgM antibody forming cell (AFC) and T cell-independent DNP-Ficoll-induced AFC responses. These data support a concentration-dependent bifunctional effect by TGF-beta(1) on humoral immune responses in vitro. We further investigated a putative mechanistic role for Smad3, an intracellular mediator of TGF-beta(1) signaling, in propagating the inhibitory effects of TGF-beta(1) on humoral immune responses. Relative to wild type littermates, splenocytes from mice homologous for a null mutation in the gene encoding the TGF-beta receptor-activated Smad3 (Smad3(Exon8-/-)) were less sensitive to inhibition by TGF-beta(1) following anti-sRBC- and LPS-sensitization in vitro. In agreement, inhibition of IgM protein production by TGF-beta(1) was also dampened in LPS-sensitized Smad3(Exon8-/-) splenic B cells. Moreover, stimulation of IgA by TGF-beta(1) was abrogated in LPS-sensitized Smad3(Exon8-/-) splenocytes suggesting an additional role for Smad3 in regulating IgA production in vitro. Our results suggest that the effects of TGF-beta(1) on humoral immune responses fundamentally differ in a concentration-dependent manner and are mediated, in part, through Smad3 signaling. (C) 2003 Elsevier B.V. All rights reserved.