BACKGROUND: The immunosuppressive macrolide tacrolimus (FK506) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings. More recently, successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported. OBJECTIVES: We explored the effects of this compound on epidermal Langerhans' cells (LCs), which are known to play an important pathophysiologic role in inflammatory skin diseases. METHODS: The expression of the intracellular FK506 binding protein (FKBP12) was monitored on freshly isolated and cultured epidermal LCs. Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta-methasone valerate (betaMv) were performed. RESULTS: FKBP12 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells. Tacrolimus inhibited the expression of IL-2R (CD25) and of the costimulatory molecules CD80 (B7.1) and CD40. Expression of MHC class I and II was also affected, whereas CD86 (B7.2) expression was not altered. In contrast, betaMv strongly increased the expression of CD25. Paradoxically, while decreasing CD40 and MHC class I expression, betaMv significantly increased the expression of MHC class II, CD80, and CD86 on cultured LCs but impaired their allostimulatory activity. Tacrolimus was about 100 times more potent than betaMv at inhibiting LC stimulatory function. CONCLUSION: Tacrolimus can exert immunopharmacologic alterations on LCs, which may account, at least in part, for the therapeutic effect of this compound in eczematous skin diseases.
BACKGROUND: The immunosuppressive macrolidetacrolimus (FK506) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings. More recently, successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported. OBJECTIVES: We explored the effects of this compound on epidermal Langerhans' cells (LCs), which are known to play an important pathophysiologic role in inflammatory skin diseases. METHODS: The expression of the intracellular FK506 binding protein (FKBP12) was monitored on freshly isolated and cultured epidermal LCs. Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta-methasone valerate (betaMv) were performed. RESULTS:FKBP12 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells. Tacrolimus inhibited the expression of IL-2R (CD25) and of the costimulatory molecules CD80 (B7.1) and CD40. Expression of MHC class I and II was also affected, whereas CD86 (B7.2) expression was not altered. In contrast, betaMv strongly increased the expression of CD25. Paradoxically, while decreasing CD40 and MHC class I expression, betaMv significantly increased the expression of MHC class II, CD80, and CD86 on cultured LCs but impaired their allostimulatory activity. Tacrolimus was about 100 times more potent than betaMv at inhibiting LC stimulatory function. CONCLUSION:Tacrolimus can exert immunopharmacologic alterations on LCs, which may account, at least in part, for the therapeutic effect of this compound in eczematous skin diseases.
Authors: Jonas T Schnider; Matthias Weinstock; Jan A Plock; Mario G Solari; Raman Venkataramanan; Xin Xiao Zheng; Vijay S Gorantla Journal: Clin Dev Immunol Date: 2013-02-13