Gautam S C, Noth C J, Janakiraman N, Pindolia K R, Chapman R A
Department of Medicine, Henry Ford Hospital, Detroit, MI 48202, USA.
Exp Hematol. 1995 Jun;23(6):482-91.
Bone marrow stromal cells produce cytokines that are essential for the proliferation and differentiation of hematopoietic stem and progenitor cells. Thus, regulation of cytokine production by bone marrow accessory cells is a critical aspect of stromal cell regulation of hematopoiesis. We have investigated the effect of two cytokines that have been demonstrated to modulate factor production by non-marrow accessory cells (i.e., transforming growth factor-beta 1 [TGF-beta 1] and interleukin-4 [IL-4]) on the induced expression of cytokine mRNA in a bone marrow-derived, cloned, murine stromal cell line +/+/-.LDA11. We showed that +/+/-.LDA11 cells can be induced with lipopolysaccharide (LPS), IL-1 alpha, or interferon-gamma (IFN-gamma) to express mRNA for monocyte chemoattractant protein-1 (MCP-1/JE), IFN-inducible protein-10 (IP-10), stem cell factor (SCF), and macrophage colony-stimulating factor (M-CSF) but not for IL-1 alpha, IL-3, or tumor necrosis factor-alpha (TNF-alpha). The expression of MCP-1/JE and IP-10 mRNA by these inducers was potentiated by TGF-beta 1 and IL-4. The augmentation by TGF-beta 1 of both mRNAs induced with IL-1 alpha was maximum when applied to the cells concurrently with the inducer; the IFN-gamma-induced expression of mRNAs was augmented even if the addition of TGF-beta 1 was delayed. Similarly, IL-4 potentiation of both mRNAs by either inducer progressively increased as the time between exposure to the inducer and exposure to IL-4 increased. Neither modulator altered the time course of mRNA expression by either inducer. TGF-beta 1- and IL-4-mediated augmentation of MCP-1/JE mRNA by IL-1 alpha or IFN-gamma was partially reversed by cycloheximide (CHX), whereas potentiation of IP-10 by either modulator remained unaffected. Increase in the stability of mRNA transcripts by TGF-beta 1 or IL-4 does not appear to play a role in the enhanced accumulation of mRNA in the presence of the modulators. These findings support a role for TGF-beta 1 and IL-4 as critical regulatory molecules in production of MCP-1 and IP-10 chemokines by stromal cells.
骨髓基质细胞产生的细胞因子对造血干细胞和祖细胞的增殖与分化至关重要。因此，骨髓辅助细胞对细胞因子产生的调控是基质细胞调控造血过程的关键环节。我们研究了两种已被证明可调节非骨髓辅助细胞因子产生的细胞因子（即转化生长因子-β1 [TGF-β1] 和白细胞介素-4 [IL-4]）对源自骨髓的克隆小鼠基质细胞系 +/+/-.LDA11 中细胞因子 mRNA 诱导表达的影响。我们发现，+/+/-.LDA11 细胞可被脂多糖（LPS）、IL-1α 或干扰素-γ（IFN-γ）诱导表达单核细胞趋化蛋白-1（MCP-1/JE）、IFN 诱导蛋白-10（IP-10）、干细胞因子（SCF）和巨噬细胞集落刺激因子（M-CSF）的 mRNA，但不表达 IL-1α、IL-3 或肿瘤坏死因子-α（TNF-α）的 mRNA。TGF-β1 和 IL-4 增强了这些诱导剂诱导的 MCP-1/JE 和 IP-10 mRNA 的表达。当与诱导剂同时作用于细胞时，TGF-β1 对 IL-1α 诱导的两种 mRNA 的增强作用最大；即使延迟添加 TGF-β1，IFN-γ 诱导的 mRNA 表达也会增强。同样，随着诱导剂暴露与 IL-4 暴露之间时间间隔的增加，IL-4 对两种诱导剂诱导的 mRNA 的增强作用逐渐增强。两种调节剂均未改变任何一种诱导剂诱导的 mRNA 表达的时间进程。环孢霉素（CHX）部分逆转了 TGF-β1 和 IL-4 介导的 IL-1α 或 IFN-γ 对 MCP-1/JE mRNA 的增强作用，而两种调节剂对 IP-10 的增强作用不受影响。TGF-β1 或 IL-4 导致的 mRNA 转录本稳定性增加似乎在调节剂存在时 mRNA 积累增强过程中不起作用。这些发现支持 TGF-β1 和 IL-4 作为基质细胞产生 MCP-1 和 IP-10 趋化因子的关键调节分子的作用。
