Pin1 modulates the type 1 immune response.
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.


RESULTS
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
These data suggest Pin1 inhibitors should be explored for use as immunosuppressants and employed with available calcineurin inhibitors to reduce toxicity and enhance effectiveness.
Esnault
Stephane
S
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
Braun
Ruedi K
RK
Shen
Zhong-Jian
ZJ
Xiang
Zhuzai
Z
Heninger
Erika
E
Love
Robert B
RB
Sandor
Matyas
M
Malter
James S
JS
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D016040:Lung Transplantation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D018417:Th1 Cells / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects; D014184:Transplantation, Homologous / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C091326:Cxcl10 protein, rat; D007376:Interleukin-2; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; C414604:PDZD2 protein, rat; D012333:RNA, Messenger; D007371:Interferon-gamma; D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C005134:juglone