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Effects of Endogenously Activated Transforming Growth Factor-ß on Growth and Differentiation of Retinoic Acid-treated HL-60 Cells¹

Department of Cell Biology and Kaplan Cancer Center, and the Raymond and Beverly Sackler Foundation Laboratory, New York University Medical Center, New York, New York 10016 [I. N., D. B. R.] and RIKEN, Tsukuba Life Science Center, Institute of Physical and Chemical Research, 3-1-1 Koyadai, Tsukuba, Ibaraki 305, Japan [S. K.]

Retinoic acid (RA)-treated HL-60 cells were used as a model to study differentiation of granulocytic leukemias. RA induces these cells to mature into granulocytes and to decrease growth. Mediators of these RA effects have not been identified definitively, but transforming growth factor-ß (TGF-ß) has been implicated in regulating proliferation and differentiation of myelogenous leukemic cells. The role of TGF-ß in RA-dependent differentiation and cessation of growth was examined by adding neutralizing anti-TGF-ß IgG to RA-treated HL-60 cells, followed by assessing cell growth and markers of granulocytic differentiation over 5 days. After addition of neutralizing anti-TGF-ß IgG, growth of RA-treated HL-60 cells was maintained at control levels, but granulocytic differentiation continued. These experiments demonstrated that the antiproliferative activity of RA was TGF-ß dependent but that differentiation was not. Because most cell types secrete TGF-ß in a biologically inactive complex, a TGF-ß-dependent effect requires cells to activate the latent form of TGF-ß. Active and total TGF-ß levels were quantitated in media harvested from control and RA-treated cells using a luciferase-based bioassay for TGF-ß activity. Similar levels of total TGF-ß were observed between control and RA-treated cells. RA-treated cells produced active TGF-ß (18–24 pg/ml) after 1, 2, and 3 days of treatment, whereas negligible levels were produced by control cultures. Activation of endogenous latent TGF-ß by RA-treated cells occurred through a plasmin-independent mechanism.

¹ Supported by NIH Grants CA 23753 (D. B. R.), EY-06537 (I. N.), and T32GM 07238 (I. N.).

² To whom requests for reprints should be addressed, at Department of Cell Biology, MSB 650, New York University Medical Center, 550 First Avenue, New York, NY 10016.

Received 9/28/95. Accepted 12/12/95.

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