Heparin markedly enhances generation of cytotoxic T lymphocytes against allogeneic cells and histocompatible tumors. In this study, we demonstrated a marked synergism between heparin and low concentrations of recombinant IL-1-α and IL-1-β in enhancement of cytotoxic T cell responses in mice. Low molecular weight (8000 Da) dextran sulfate also enhanced the T cell responses and synergized with IL-1, whereas, de-N-sulfated heparin was devoid of both of these activities. The synergistic effect was selective for IL-1, because there was no synergism between heparin or dextran sulfate and other cytokines (tumor necrosis factor-α, IL-4, and, as shown previously, IL-2). Heparin did not increase the production of IL-1 (and IL-2, as shown before). Heparin did not bind to IL-1, despite significant amino acid homology between IL-1 and heparin-binding endothelial cell growth factors. Heparin enhanced the growth-promoting effect of IL-1 on the IL-1-dependent helper T cell clone, D10.G4.1, and enhanced IL-1 receptor expression on these cells. These data indicate that heparin acts directly on the T cells and enhances their responsiveness to IL-1 by up-regulating IL-1 receptor expression.
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