Pharmacological studies on prodigiosin a new immunisuppressant

Abstract

Immunosuppressants are a class of compounds that reduce the effects of an activated immune system. These compounds have been clinically effective in suppressing the organ graft rejection and in the treatment of autoimmune diseases. The most widely used class of immunosuppressants is the natural products originally isolated from cultures of microorganisms. Among them, cyclosporin A, FK-506, and rapamycin are the most well known immunosuppressants. In the course of screening for immunosuppressants from microorganisms, we isolated prodigiosin (PDG) from the culture broth of Serratia marcescens. This study was directed at investigating pharmacological and toxicological properties of PDG. Almost all current immunosuppressive drugs target T cells, since these cells are crucial in the initiation and progression of both graft rejection and autoimmune diseases. Thus, we first investigated cell-type specificity of PDG. PDG selectively inhibited concanavalin A (Con A)-induced T cell proliferation, but had little effect on lipopolysaccharide (LPS)-induced B cell proliferation. In addition, PDG selectively inhibited the T cell-mediated immune functions such as mixed lymphocyte response and specific IgM production to T-dependent antigen sheep red blood cells. However, PDG did not affect LPS-induced polyclonal IgM antibody production of B cells and LPS-induced NO production of macrophages. We verified that PDG at fully active concentration (＜30 ng/ml) did not induce cell death as determined by propidium iodide uptake experiment. PDG also did not show toxicity in vivo to lymphoid organs at effective dosages (＜30 mg/kg). These results suggested that PDG was T cell specific immunosuppressants. We further investigated the mechanism of action of PDG in T cells. As a first step towards understanding the mode of action of PDG in T cells, we investigated the effect of PDG on the IL-2/IL-2R autocrine pathway, because the synthesis and action of IL-2 were the major targe...