TRANSFORMING GROWTH-FACTOR-BETA-1 INHIBITS EXPRESSION OF THE GENE-PRODUCTS FOR STEEL FACTOR AND ITS RECEPTOR (C-KIT)

Transforming growth factor beta 1 (TGF-beta 1), a product of marrow st romal cells, inhibits the proliferation and differentiation of hematop oietic progenitor cells within the hematopoietic microenvironment. Ste el factor (SF), also a product of marrow stromal cells, is an essentia l positive regulator of hematopoiesis in vivo. TGF-beta 1 has been sho wn to repress human and murine leukemic cell and murine lin(-) bone ma rrow mononuclear cell expression of the receptor for SF (c-kit). We sp eculated that TGF-beta 1 might exert its inhibitory effect on hematopo iesis in part by decreasing SF/c-kit interactions. Therefore, we teste d the hypothesis that TGF-beta 1 inhibits both stromal cell expression of SF and hematopoietic progenitor cell expression of c-kit. We measu red stromal cell expression of SF protein and hematopoietic progenitor cell expression of membrane-bound c-kit before and after exposure to recombinant human TGF-beta 1. Both stromal cell expression of SF prote in and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot and ribonuclea se protection assays, we determined that TGF-beta 1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1 wa s also found to repress c-kit mRNA in human leukemic myeloblasts as we ll as in normal lin(-) hematopoietic progenitor cells. In contrast wit h its effect on SF mRNA, TGF-beta 1 accelerated the degradation of c-k it mRNA. We conclude that TGF-beta 1 inhibits stromal cell production of SF by repression of SF gene transcription and represses hematopoiet ic progenitor cell expression of c-kit by decreasing the stability of c-kit transcripts. Taking into account the importance of SF and c-kit in maintaining steady-state hematopoiesis in vivo, the dual effect of IGF-beta 1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-beta 1 inhibits hematopoiesis in vi vo. (C) 1995 by The American Society of Hematology.