Prodigiosin blocks T cell activation by inhibiting interleukin-2R alpha expression and delays progression of autoimmune diabetes and collagen-inducedarthritis

Prodigiosin (PDG) was previously reported to be a T cell-specific immunosup pressant. Here we describe the mechanism of action of PDG in T cells and th e effect of PDG on autoimmune diseases. PDG selectively suppresses concanav alin A (Con A)-induced T cell proliferation, but has little effect on lipop olysaccharide-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-2R alpha) e xpression, and this results in a disruption of the IL-2/IL-2R signaling pat hway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting i nterferon-gamma and IL-4 as well as into effector cytotoxic T lymphocytes e xpressing perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activ ator 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 markedl y reduced blood glucose levels and cellular infiltration into the pancreati c islets in nonobese diabetic mice, and that it also delays the onset of co llagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstr ate that PDG has a unique mode of action, namely, that it blocks T cell act ivation by inhibiting primarily IL-2R alpha expression in the IL-2/ IL-2R s ignaling, and show that this compound represents a promising immunosuppress ant candidate for the treatment of autoimmune diseases.