Transforming growth factor-β1 down-regulates expression of chemokine stromal cell–derived factor-1: functional consequences in cell migration and adhesion

Abstract

Chemokine stromal cell-derived factor-1 (SDF-1) is expressed by bone marrow (BM) stromal cells and plays key roles in BM cell migration. Modulation of its expression could affect the migratory capacity of cells trafficking the BM, such as hematopoietic progenitor and leukemic cells. Transforming growth factor-beta1 (TGF-beta1) is present in the BM environment and constitutes a pivotal molecule controlling BM cell proliferation and differentiation. We used the BM stromal cell line MS-5 as a model to investigate whether SDF-1 expression constitutes a target for TGF-beta1 regulation and its functional consequences. We show here that TGF-beta1 down-regulates SDF-1 expression, both at the mRNA level, involving a decrease in transcriptional efficiency, and at the protein level, as detected in lysates and supernatants from MS-5 cells. Reduction of SDF-1 in supernatants from TGF-beta1-treated MS-5 cells correlated with decreased, SDF-1-dependent, chemotactic, and transendothelial migratory responses of the BM model cell lines NCI-H929 and Mo7e compared with their responses to supernatants from untreated MS-5 cells. In addition, supernatants from TGF-beta1-exposed MS-5 cells had substantially lower efficiency in promoting integrin alpha4beta1-mediated adhesion of NCI-H929 and Mo7e cells to soluble vascular cell adhesion molecule-1 (sVCAM-1) and CS-1/fibronectin than their untreated counterparts. Moreover, human cord blood CD34+ hematopoietic progenitor cells displayed SDF-1-dependent reduced responses in chemotaxis, transendothelial migration, and up-regulation of adhesion to sVCAM-1 when supernatants from TGF-beta1-treated MS-5 cells were used compared with supernatants from untreated cells. These data indicate that TGF-beta1-controlled reduction in SDF-1 expression influences BM cell migration and adhesion, which could affect the motility of cells trafficking the bone marrow.

MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells

“…The findings extend data that were reported by Wright et al in the murine BMSC cell line MS-5. The authors described an early inhibitory effect of TGFB1 on the promoter of the CXCL12 gene which was counteracted by CXCL-12 mRNA increments after 12 h. 32 In the primary hBMSC culture, we observed a suppressive effect of TGFB1 on CXCL12 levels which was maintained for at least 24 h and was, therefore, long-lasting (data not shown). We speculated that the TGFB1-associated effect is pronounced by the activity of inhibitory miRNAs.…”

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

“…Myeloma cells increase Th3 cytokine response by secreting TGFβ1, which causes defective Th1 and Th2 cytokine responses, therefore a significant suppression of the immune system is seen (26). TGFβ1 is present in the bone marrow (BM) environment and constitutes a pivotal molecule controlling BM cell proliferation and differentiation (27). Study in MM showed that IL-2 and IL-4 levels in patients were lower than those in the normal controls, whereas TGFβ1 level were higher than that in controls (3)(4)(5).…”

The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis

“…78 Conversely, the expression of SDF-1 was found to be downregulated by steroids, 79 G-CSF 80 and transforming growth factor (TGF)-b1. 81 On the other hand, it was reported that low levels of TGF-b1 can modulate SDF-1 responsiveness of CD34 þ cells and thus facilitate SDF-1-mediated retention and nurturing of stem/progenitor cells in BM. 82 As a strong correlation exists between chronic inflammation and tumor progression/metastasis, inflammation-driven expression of SDF-1 may also play an important role in dissemination/ metastasis of CSC.…”