Inhibition by chlorpromazine of lymphokine-specific mRNA expression in human thymocytes

Abstract

This study was designed to determine the effect of the phenothiazine chlorpromazine (CPZ) on the activation of human thymocytes. We provide evidence that CPZ inhibits the accumulation of mRNA specific for the lymphokines, interleukin 2, interferon-gamma, tumor necrosis factor alpha and the proto-oncogene c-myc; by contrast, the accumulation of mRNA specific for the alpha chain of the interleukin 2 receptor and the subsequent early expression of Tac antigen on the cell surface is not inhibited by CPZ. The inhibition of the expression of lymphokine-specific mRNA results in a decrease in interferon-gamma synthesis and in inhibition of thymocyte proliferation as determined by the incorporation of [3H]thymidine. In addition, we show that activation of protein kinase C (PKC) in human thymocytes by 12-O-tetradecanoyl phorbol 13-acetate (TPA) causes the phosphorylation of a protein of a molecular mass of approximately 75 kDa. The function of this protein is as yet not defined, but it is possible that it plays a role in the transduction of the signals to the nucleus which in turn elicit the expression of the genes coding for c-myc and for the lymphokines required for thymocyte activation. We also demonstrate that CPZ, like the immunosuppressant drug cyclosporin A does not inhibit the phosphorylation of the 75-kDa protein which is induced by the activation of PKC by TPA and does not affect phosphoinositide breakdown, indicating that it exerts its effect at a site distal to the activation of PKC. These observations demonstrate that CPZ has an immunoregulatory function in addition to its psychotropic activity.