The emerging importance of immunophilins in fibrosis development

Abstract

Immunophilins are a family of proteins encompassing FK506-binding proteins (FKBPs) and cyclophilins (Cyps). FKBPs and Cyps exert peptidyl-prolyl cis-trans isomerase (PPIase) activity, which facilitates diverse protein folding assembly, or disassembly. In addition, they bind to immunosuppressant medications where FKBPs bind to tacrolimus (FK506) and rapamycin, whereas cyclophilins bind to cyclosporin. Some large immunophilins have domains other than PPIase referred to as tetratricopeptide (TPR) domain, which is involved in heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp 70) chaperone interaction. The TPR domain confers immunophilins' pleotropic actions to mediate various physiological and biochemical processes. So far, immunophilins have been implicated to play an important role in pathophysiology of inflammation, cancer and neurodegenerative disorders. However, their importance in the development of fibrosis has not yet been elucidated. In this review we focus on the pivotal functional and mechanistic roles of different immunophilins in fibrosis establishment affecting various organs. The vast majority of the studies reported that cyclophilin A, FKBP12 and FKBP10 likely induce organ fibrosis through the calcineurin or TGF-β pathways. FKBP51 demonstrated a role in myelofibrosis development through calcineurin-dependant pathway, STAT5 or NF-κB pathways. Inhibition of these specific immunophilins has been shown to decrease the extent of fibrosis suggesting that immunophilins could be a novel promising therapeutic target to prevent or reverse fibrosis.

Keywords: Cyclophilin A; Cyclosporin A; FK506; FKBP12; Fibrosis; Immunophilins.

Fig. 1

Cyclophilin A and FKBP12 activate T cells which induce fibrosis. Calcineurin (CaN) activity is regulated by Ca + 2/calmodulin. After the engagement of T-cell receptor with its ligand, intracellular Ca + 2 level will interact with calcineurin (CaN) and activates nuclear factor-activated T-cells (NFAT) family members. NFAT then translocate into the nucleus and activate gene expression of cytokines including IL-2, IL-4, and CD40L which then activate fibroblasts differentiation to myofibroblasts which induce extracellular matrix (ECM) synthesis and remodelling to induce fibrosis. Inhibition of CaN pathway with cyclosporin A (CsA) or FK506 will supress fibrosis

Fig. 2

Cyclophilin A activates JNK and MAPK-P38 which induce liver fibrosis. Cyclophilin A activates phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) which induce hepatic stellate cells (HSCs) growth and collagen production that induce liver fibrosis. Cyclosporin A inhibited cell growth and collagen production which was associated with suppressed phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs)