title: Pin1 modulates the type 1 immune response.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Stephane
authors.initials: S
authors.lastname: Esnault
authors.forename: Ruedi K
authors.initials: RK
authors.lastname: Braun
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Shen
authors.forename: Zhuzai
authors.initials: Z
authors.lastname: Xiang
authors.forename: Erika
authors.initials: E
authors.lastname: Heninger
authors.forename: Robert B
authors.initials: RB
authors.lastname: Love
authors.forename: Matyas
authors.initials: M
authors.lastname: Sandor
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
mesh_terms: 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
chemical_list: 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