Loss of transforming growth factor beta 1 receptors and its effects on the growth of EBV-transformed human B cells.
Transforming growth factor-beta (TGF-beta) is a potent negative regulator of normal human B cell growth mediated by exogenous signals, including IL-2 and low m.w. B cell growth factor 12 kDa (BCGF-12 kDa). In the present study, we investigated the regulatory linkage between viral or nonviral transformation of human B cells and the growth inhibitory effects of TGF-beta 1. A panel of EBV+ and EBV- B cell lines, derived either by in vitro EBV B cell transformation, or from cases of lymphoma was used to quantitate the negative growth effects of TGF-beta 1. The proliferative response of three EBV- B cell lines to rBCGF-12 kDa or serum was inhibited by low concentrations of TGF-beta 1 (0.2-0.5 ng/ml for 50% maximal effect), as measured by tritiated thymidine uptake and viable cellular recovery. In contrast, rBCGF-12 kDa or serum mediated proliferation of three EBV+ B cell lines was refractory to the growth inhibitory effects of TGF-beta 1. In an attempt to understand the mechanism(s) for this differential growth control in EBV+ and EBV- B cells, we studied the expression of TGF-beta 1, c-myc, and TGF-beta 1 receptors. No correlation was observed between the expression of TGF-beta 1 or c-myc gene and growth inhibition by TGF-beta 1 in the cell lines studied. Our results indicate that sensitivity or resistance to TGF-beta 1 correlated with the presence or absence (loss) of high affinity receptors for TGF-beta 1. EBV- B cell lines expressed levels of high affinity receptors similar to those found on activated normal B or T cells. In contrast, EBV+ B cell lines showed no detectable high affinity receptors. Chemical cross-linking studies with a bifunctional reagent, dissuccinimidyl suberate revealed a normal expression of type I (65-70 kDa), type II (85-90 kDa), and type III (280-300 kDa) TGF-beta 1 high affinity receptors on EBV- B cell lines. In contrast, EBV+ B cell lines did not express type I and type II receptors, whereas type III receptors were expressed but could not be inhibited by unlabeled TGF-beta 1.(ABSTRACT TRUNCATED AT 400 WORDS)
Kumar
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Department of Pathology, Roger Williams Medical Center-Brown University, Providence, RI 02908.
Rogers
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T
Maizel
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Sharma
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S
D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002472:Cell Transformation, Viral; D004305:Dose-Response Relationship, Drug; D016259:Genes, myc / Q000235:genetics; D004854:Herpesvirus 4, Human; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012313:RNA / Q000032:analysis; D011956:Receptors, Cell Surface / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology; D014178:Translocation, Genetic
D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D012313:RNA