Abundant expression of transforming growth factor-β1 and -β2 by Hodgkin's reed-sternberg cells and by reactive T lymphocytes in Hodgkin's disease

Abstract

The depressed cellular immunity observed in patients with Hodgkin's disease (HD) has been attributed to production of transforming growth factor (TGF)-β or TGF-β-like substances by Hodgkin's Reed-Sternberg (H-RS) cells. The TGF-β produced by L-428 cells (an H-RS cell line) is a 130-kd molecular weight glycoprotein that apparently differs from the TGF-β (molecular weight, 25 kd) produced by most lymphoid and hematopoietic cells. Among several distinct types of TGF-β that have been purified, only TGF-β1 and TGF-β2 have thus far been identified in hematopoietic cells. By using monoclonal antibodies (1D11 and 3C7) and oligonucleotide probes specific for TGF-β1 and TGF-β2, we confirmed that a cultured H-RS cell line, KM-H2, can produce both TGF-β types, whereas another line, HDLM-1, produces only TGF-β1. Despite the abundance of mRNA in both of these cells, only small amounts of TGF-β activity were detected, probably because of rapid degradation of TGF-β1 mRNA by specific nuclease. No degraded TGF-β2 RNA products were observed in KM-H2 cells. The TGF-β produced by both types of H-RS cells had a molecular weight of approximately 25 kd. In tissues expression of TGF-β was observed in a small portion (30%) of H-RS cells in 16 of 20 cases examined. A large number of small to medium-sized lymphoid cells (T lymphocytes) in tissues involved by HD also were positive for TGF-β. These results indicate that there is functional heterogeneity among H-RS cells, and that H-RS cells are not the only source of TGF-β in tissues involved by HD. Hodgkin's Reed-Sternberg cells are known to secrete several other cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-α. These cytokines could be responsible for the increased number of T lymphocytes in tissues involved by HD. Furthermore, T lymphocytes can respond to IL-1 and IL-6 secreted by H-RS cells by increasing their production of TGF-β. Abundant expression of TGF-β by T lymphocytes was not observed in lymphoid tissues other than those involved by HD.