Transforming growth factor-β1: Differential effects on multiple myeloma versus normal B cells

Abstract

Interleukin-6 (IL-6), a product of bone marrow stromal cells (BMSCs), is a growth factor for multiple myeloma (MM) cells. Transforming growth factor- β1 (TGF-β1) is also produced by BMSCs and can regulate IL-6 secretion by several tissues, including BMSCs. The present study was designed to characterize in vitro tumor growth regulation by TGF-β1 in MM. Sorted CD38+CD45RA- MM cells secreted significantly more TGF-β1 (8.2 ± 2.0 ng/mL) than peripheral blood mononuclear cells (P < .001), splenic B cells (P < .091), and CD40 ligand (CD40L) pretreated B cells (P < .92, n = 6). TGF-β1 secretion was correlated with IL-6 secretion in MM-BMSCs. Anti-TGF-β1 monoclonal antibody both blocked IL-6 secretion by BMSCs and inhibited the increments in IL-6 secretion by BMSCs induced by MM cell adhesion. Moreover, exogenous TGF- β1 upregulated IL-6 secretion by MM-BMSCs, normal BMSCs, and CD38+ CD45RA- MM cells, as well as tumor cell proliferation. This is in contrast to the inhibitory effect of TGF-β1 on proliferation and Ig secretion of normal splenic B cells. Finally, retinoblastoma proteins (pRB) are constitutively phosphorylated in MM cells; TGF-β1 either did not alter or increased pRB phosphorylation. pRB are dephosphorylated in splenic B cells and phosphorylated in CD40L triggered B cells; in contrast to its effects on MM cells, TGF-β1 decreased phosphorylation of pRB in CD40L treated B cells. These results suggest that TGF-β1 is produced in MM by both tumor cells and BMSCs and can trigger IL-6 secretion by both MM cells and BMSCs, with related tumor cell growth. Moreover, MM cell growth may be enhanced by resistance of tumor cells to the inhibitory effects of TGF-β1 on normal B-cell proliferation and Ig secretion.