Pin1 Modulates the Type 1 Immune Response

Abstract

Background/AbstractImmune 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 FindingsWe 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/SignificanceThese data suggest Pin1 inhibitors should be explored for use as immunosuppressants and employed with available calcineurin inhibitors to reduce toxicity and enhance effectiveness.

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

“…2C). These results were consistent with the previous reports showing Pin1 inhibition selectively suppressed IFN-␥ expression in bronchoalveolar lavage cells (23,24). We then established Pin1-overexpressing human primary chondrocytes using ankle tissues obtained during surgery in an osteoarthritic patient.…”

“…2C). It has been shown that Pin1 knockout mice show both Th1 and Th2 abnormalities (23). Hence, we additionally determined the mRNA expression of IFN-␥ (Th1 dependent) and IL-4 production (Th2 dependent) in both GFP-HTB94 and Pin1-HTB94 cells.…”

Pin1 Protein Regulates Smad Protein Signaling and Pulmonary Fibrosis

“…cently, we showed significantly reduced collagen deposition in the airways or plura of Pin1 null rodents after the induction of allergic asthma or MHC-mismatched lung transplantation, respectively (9,10). Therefore, we assessed if Pin1 was also important for interstitial fibrosis and thus assessed the effects of BLM, which models many features found in human IPF (15).…”

“…The altered expression of MMPs and TIMPs suggests an involvement of Pin1 in TGF-␤1 signaling and Fb gene regulation (10). Because resident Fb account for 30% of total lung cells and are the main producer of ECM (22), we established primary lung Fb cultures from wildtype and Pin1 Ϫ/Ϫ mice.…”

“…We have shown that Pin1 controls the expression of inflammatory cytokine and profibrotic growth factors by activated immune cells (8,9). Pin1 blockade in vivo significantly reduced airway inflammation and pulmonary collagen deposition in animal models of asthma and lung transplantation (9,10).…”