Growth-inhibitory effects of transforming growth factor-β1 myeloid leukemia cell lines

Transforming growth factor-beta 1 is a pleiotropic cytokine involved in a variety of biological processes in both transformed and normal cells, including regulation of cellular proliferation and differentiation; its predominant action on hematopoietic cells is to inhibit cell growth. We used growth factor-dependent cell lines to assess TGF-beta 1 effects on human myeloid leukemia cell growth. While four lines were completely or predominantly resistant, TGF-beta 1 inhibited effectively, albeit to various extents, the growth of 12 other cell lines. This effect was dose dependent and specific, because a neutralizing anti-TGF-beta 1 antibody prevented TGF-beta 1-induced growth suppression. In the present system: basic fibroblast growth factor, known as an antagonist of TGF-beta 1 counteracting its inhibitory effects, did not abrogate the suppressive effects of TGF-beta 1. Other growth-stimulatory cytokines negated the TGF-beta 1-induced inhibition in several cell lines, again to various extents. When proliferation was enhanced by growth-promoting cytokines (e.g. granulocyte-macrophage colony-stimulating factor, GM-CSF, stem cell factor, SCF, or PIXY-321), some previously TGF-beta 1-sensitive cell lines acquired cellular resistance toward TGF-beta 1-mediated growth suppression, whereas four other cell lines remained susceptible to TGF-beta 1 growth inhibition despite possible counteraction by other cytokines. Thus, three growth response patterns to TGF-beta 1 were seen: (1) constitutive resistance; (2) factor-dependent relative resistance; and (3) sensitivity to growth inhibition indifferent to counteracting cytokines. In the latter case, TGF-beta 1 did not downregulate expression of one specific growth factor receptor. These studies indicate that human myeloid leukemia cells, represented here by leukemia cell lines as model systems, exhibit heterogeneous growth responses to TGF-beta 1; its inhibitory effects can be modulated or completely alleviated by positive antagonistic cytokines. The availability of TGF-beta 1-susceptible and -refractory cell lines allows for detailed investigations on the mechanisms of these regulatory pathways, the nature of TGF-beta 1-resistance, and the possible contribution of acquired TGF-beta 1-resistance to disease progression. (C) 1998 Elsevier Science Ltd. All rights reserved.