Pin1 modulates the type 1 immune response

Stephane Esnault, Ruedi K. Braun, Zhong Jian Shen, Zhuzai Xiang, Erika Heninger, Robert B. Love, Matyas Sandor, James S. Malter

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30 Scopus citations

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. 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-γ, 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-γ 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.

Original languageEnglish (US)
Article numbere226
JournalPloS one
Volume2
Issue number2
DOIs
StatePublished - Feb 21 2007

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Esnault, S., Braun, R. K., Shen, Z. J., Xiang, Z., Heninger, E., Love, R. B., Sandor, M., & Malter, J. S. (2007). Pin1 modulates the type 1 immune response. PloS one, 2(2), [e226]. https://doi.org/10.1371/journal.pone.0000226