Abstract
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 α-chain (IL-2Rα) 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-γ 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-κB, 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-2Rα expression in the IL-2/IL-2R signaling, and show that this compound represents a promising immunosuppressant candidate for the treatment of autoimmune diseases.
Footnotes
- Abbreviations:
- Con A
- concanavalin A
- TCR
- T cell receptor
- IL
- interleukin
- IL-2Rα
- IL-2 receptor α-chain
- Jak-STAT
- Janus kinase-signal transducer and activator of transcription
- Th cells
- helper T cells
- INF-γ
- interferon-γ
- CTL
- cytotoxic T lymphocyte
- CsA
- cyclosporin A
- UP
- undecylprodigiosin
- NF-κB
- nuclear factor-κB
- AP-1
- activator protein-1
- PDG
- prodigiosin
- NOD
- nonobese diabetic
- LPS
- lipopolysaccharide
- RT-PCR
- reverse transcription-polymerase chain reaction
- PCR
- polymerase chain reaction
- ELISA
- enzyme-linked immunosorbent assay
- PE
- phycoerythrin
- FITC
- fluorescein isothiocyanate
- EMSA
- electrophoretic mobility shift assay
- NF-AT
- nuclear factor of activated T cells
- Received April 30, 2001.
- Accepted July 23, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|