Pin1 modulates the type 1 immune response. PLoS One 2007 Feb 21;2(2):e226
Date
02/22/2007Pubmed ID
17311089Pubmed Central ID
PMC1790862DOI
10.1371/journal.pone.0000226Scopus ID
2-s2.0-34548693416 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
UNLABELLED: BACKGROUND/ABSTRACT: Immune responses initiated by T cell receptor (TCR) and costimulatory molecule mediated signaling culminate in maximal cytokine mRNA production and stability. The transcriptional responses to co-stimulatory T cell signalling involve calcineurin and NF-AT, which can be antagonized by interference with the cis-trans peptidyl-prolyl isomerases (PPIase), cyclophilin A and FKBP. Signalling molecules downstream of CD28 which are essential for the stabilization of cytokine mRNAs are largely unknown.
METHODOLOGY/PRINCIPAL FINDINGS: We now show that Pin1, a third member of the PPIase family mediates the post-transcriptional regulation of Th1 cytokines by activated T cells. Blockade of Pin1 by pharmacologic or genetic means greatly attenuated IFN-gamma, IL-2 and CXCL-10 mRNA stability, accumulation and protein expression after cell activation. In vivo, Pin1 blockade prevented both the acute and chronic rejection of MHC mismatched, orthotopic rat lung transplants by reducing the expression of IFN-gamma and CXCL-10. Combined transcriptional and post-transcriptional blockade with cyclosporine A and the Pin1 inhibitor, juglone, was synergistic.
CONCLUSIONS/SIGNIFICANCE: These data suggest Pin1 inhibitors should be explored for use as immunosuppressants and employed with available calcineurin inhibitors to reduce toxicity and enhance effectiveness.
Author List
Esnault S, Braun RK, Shen ZJ, Xiang Z, Heninger E, Love RB, Sandor M, Malter JSMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Chemokine CXCL10
Cyclosporine
Graft Rejection
Interferon-gamma
Interleukin-2
Lung Transplantation
Mice
Mice, Inbred C57BL
Mice, Knockout
NIMA-Interacting Peptidylprolyl Isomerase
Naphthoquinones
Peptidylprolyl Isomerase
RNA Processing, Post-Transcriptional
RNA Stability
RNA, Messenger
Rats
Rats, Inbred F344
Rats, Inbred WKY
Th1 Cells
Transcription, Genetic
Transplantation, Homologous
