The macrolide immunosuppressants in dermatology: mechanisms of action.
Macrolides are xenobiotics, produced by soil fungi, which have immunosuppressant properties. They will probably revolutionise the treatment of inflammatory dermatoses. This article outlines the context and putative mechanisms of action of this novel class of drugs. Cyclosporin, and the structurally distinct macrolides tacrolimus and pimecrolimus (an ascomycin derivative), modulate immune-cell function by inhibiting calcineurin-dependent dephosphorylation-activation of specific nuclear factors, thus preventing transcription of pro-inflammatory cytokines. The macrolide rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling protein that controls activation of a number of proteins which direct progression of the cell cycle in response to pro-inflammatory cytokines. Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and are available in topical formulations. "Skin-specific" pimecrolimus seems not to cause systemic immunosuppression when given orally. Neither topical tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus has anti-angiogenic properties that may be beneficial to the treatment of psoriasis and perhaps skin cancer.
Marsland
Alexander M
AM
Dermatology Centre, University of Manchester School of Medicine, Hope Hospital, United Kingdom. sacha.marsland@virgin.net
Griffiths
Christopher E M
CE
D019703:Calcineurin / Q000187:drug effects*; D016572:Cyclosporine / Q000627:therapeutic use; D003872:Dermatitis / Q000188:drug therapy* / Q000276:immunology*; D003880:Dermatology / Q000379:methods; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018942:Macrolides / Q000627:therapeutic use*; D008297:Male; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D018942:Macrolides; D016572:Cyclosporine; D019703:Calcineurin; D020123:Sirolimus; D016559:Tacrolimus