TRANSFORMING GROWTH-FACTOR-BETA-1 - DIFFERENTIAL-EFFECTS ON MULTIPLE-MYELOMA VERSUS NORMAL B-CELLS

Interleukin-6 (IL-6), a product of bone marrow stromal cells (BMSCs), is a growth factor for multiple myeloma (NIM) cells. Transforming grow th factor-beta 1 (TGF-beta 1) is also produced by BMSCs and can regula te IL-6 secretion by several tissues, including BMSCs. The present stu dy was designed to characterize in vitro tumor growth regulation by TG F-beta 1 in MM. Sorted CD38(+)CD45RA(-) MM cells secreted significantl y more TGF-beta 1 (8.2 +/- 2.0 ng/mL) than peripheral blood mononuclea r cells (P < .001), splenic B cells (P < .001), and CD40 ligand (CD40L ) pretreated B cells (P < .05). TGF-beta 1 secretion by MM-BMMCs (3.8 +/- 0.9 ng/mL) was significantly greater than by N-BMMCs (1.2 +/- 0.1 ng/mL P < .001). MM-BMSCs also secreted significantly more TGF-beta 1 (6.6 +/- 2.5 ng/mL, n = 11) than N-BMSCs (4.4 +/- 0.6 ng/mL, P < .02, n = 10) and N-BMSC lines (3.9 +/- 0.2 ng/mL, P < .02, n = 6). TGF-beta 1 secretion was correlated with IL-6 secretion in MM-BMSCs. Anti-TGF- beta 1 monoclonal antibody both blocked IL-6 secretion by BMSCs and in hibited the increments in IL-6 secretion by BMSCs induced by MM cell a dhesion. Moreover, exogenous TGF-beta 1 upregulated IL-6 secretion by MM-BMSCs, normal BMSCs, and CD38(+) CD45RA(-) MM cells, as well as tum or cell proliferation. This is in contrast to the inhibitory effect of TGF-beta 1 on proliferation and Ig secretion of normal splenic B cell s. Finally, retinoblastoma proteins (pRB) are constitutively phosphory lated in MM cells; TGF-beta 1 either did not alter or increased pRB ph osphorylation. pRB are dephosphorylated in splenic B cells and phospho rylated in CD40L triggered B cells; in contrast to its effects on MM c ells, TGF-beta 1 decreased phosphorylation of pRB in CD40L treated B c ells. These results suggest that TGF-beta 1 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 ma y be enhanced by resistance of tumor cells to the inhibitory effects o f TGF-beta 1 on normal B-cell proliferation and Ig secretion. (C) 1996 by The American Society of Hematology.