Prodigiosin (PDG) was previously reported to be a T cell-specific
immunosuppressant. Here we describe the mechanism of action of PDG in T cells and the effect of PDG on
autoimmune diseases. PDG selectively suppresses
concanavalin A (Con A)-induced T cell proliferation, but has little effect on
lipopolysaccharide-induced proliferation of B cells and
nitric oxide production of macrophages. Although PDG does not block
interleukin (IL)-2 production, it efficiently inhibits
interleukin-2 receptor alpha-chain (IL-2Ralpha) expression, and this results in a disruption of the IL-2/IL-2R signaling pathway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting
interferon-gamma and
IL-4 as well as into effector cytotoxic T lymphocytes expressing
perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activator of transcription activation by inhibiting
cytokine signalings in Con A-activated T cells, although it does not inhibit the activation of
nuclear factor-kappaB, nuclear factor of activated T cells, and
activator protein-1. As direct evidence of immunosuppression in vivo, we show that PDG markedly reduced
blood glucose levels and cellular infiltration into the pancreatic islets in nonobese diabetic mice, and that it also delays the onset of
collagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstrate that PDG has a unique mode of action, namely, that it blocks T cell activation by inhibiting primarily
IL-2Ralpha expression in the IL-2/IL-2R signaling, and show that this compound represents a promising
immunosuppressant candidate for the treatment of
autoimmune diseases.