Protamine enhances the activity of human recombinant interferon-gamma

Recombinant interferon-gamma (IFN-gamma) is a potent immune regulatory cytokine and is involved in the defense against several intracellular organisms, such as Chlamydia and Toxoplasma. Furthermore IFN-gamma is able to inhibit the growth of human tumor cell lines. The ability to inhibit the growth of intracellular organisms makes the therapeutic use of recombinant human IFN-gamma in certain patient groups, such as those with chronic granulomatous disease, leprosy, and HIV infection, very attractive. We have shown recently that IFN-gamma-mediated effects can be blocked by heparin and that this inhibitory effect can be abrogated by the addition of protamine. In this report, we show that the antagonistic effect of protamine on heparin-mediated inhibition of IFN-gamma activity is mainly due to the capacity of protamine to enhance IFN-gamma activity. We found that protamine enhances the capacity of IFN-gamma to inhibit the growth of different brain tumor cell lines, to induce indolamine 2, 3-dioxygenase activity, to induce toxoplasmostasis, and to induce MHC class II antigen expression in human glioblastoma cells and in human native fibroblasts. We were able to demonstrate that IFN-gamma binds to protamine, and, therefore, we assume that the effect of protamine on IFN-gamma is due to a direct interaction between the two molecules.