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. 2012 Apr 17;9(6):355–362. doi: 10.1038/nrgastro.2012.67

Figure 1. Mechanisms of action of GCs and CaN inhibitors.

Figure 1

Mechanisms are shown in a | leukocytes and b | hepatocytes. GCs diffuse into cells and bind to the GR. The GC–GR complex translocates to the nucleus to regulate gene expression. The GC–GR complex interacts with GRE promoter elements and suppresses the expression of inflammatory genes and cytokines, such as IL-2, thereby inhibiting T-cell proliferation. Steroids facilitate HCV entry in hepatocytes by upregulating gene expression of two essential HCV entry receptors—occludin and scavenger receptor class B type I—conceivably via positive GRE promoter elements. GR and type I interferon signalling share the coregulator GRIP1. Ciclosporin A binds to cyclophilin, while tacrolimus binds to FK506-binding protein, forming a complex to block calcineurin. Suppression of the serine/threonine phosphatase activity of calcineurin results in inhibition of TCR/CD3 induced T-cell proliferation by blockage of IL-2 production. Ciclosporin A binds to cyclophilin A and cyclophilin B to block the function of NS2, NS5A or NS5B to affect viral replication in hepatocytes. Protein phosphorylation induced by signal transduction is indicated by P in orange. Abbreviations: AP1, activator protein 1; CaN, calcineurin; CsA, ciclosporin A; CyP, cyclophilin; FKPB, FK506-binding protein; GC, glucocorticosteroid; GR, cytoplasmic receptor; GRE, glucocorticoid response element; GRIP1, glucocorticoid receptor-interacting protein 1, IRF9, interferon regulatory factor 9; ISG, interferon-stimulated gene; ISRE, interferon stimulated response element; JAK1, Janus kinase 1; LD, lipid droplet; NF-ATc, nuclear factor of activated T cells; NFκB, nuclear factor κB; NS, nonstructural protein; SR-BI, scavenger receptor class B type I; STAT, signal transducers and activators of transcription; Tac, tacrolimus; TCR, T-cell receptor; TYK2, nonreceptor tyrosine-protein kinase.