Recently, it has been shown that the immunosuppressive
macrolide lactone,
FK506, exerts good therapeutic efficacy in inflammatory
skin diseases. The aim of this study was to analyze the influence of topical
FK506 on molecular (IL-1alpha, IL-1beta, IL-2, IL-4,
IL-12 p35,
IL-12 p40,
macrophage inflammatory protein-2 (MIP-2), granulocyte-macrophage
CSF (GM-CSF),
TNF-alpha, and IFN-gamma) and cellular (I-A+/CD80+, I-A+/CD54+, I-A+/CD69+, I-A+/B220+, and CD4+/CD25+) events in epidermal (EC) and local draining lymph node (LNC) cells during primary
contact hypersensitivity responses.
Cytokine mRNA levels for IL-1alpha, IL-1beta,
GM-CSF,
TNF-alpha, MIP-2, and IFN-gamma in EC and for
IL-2,
IL-4,
IL-12 p35,
IL-12 p40, and IFN-gamma in LNC were increased and resulted in significant LNC proliferation during
oxazolone-induced
contact hypersensitivity. Topical
FK506 treatment dose-dependently suppressed
oxazolone-induced LNC proliferation. This effect was correlated with decreased IL-1alpha, IL-1beta,
GM-CSF,
TNF-alpha, MIP-2, and IFN-gamma
mRNA expression within the epidermis and decreased
IL-12 p35 and p40
mRNA expression in LNC. Further analysis of the LNC
cytokine pattern revealed that the production of both Thl (IFN-gamma and IL-2) and Th2 (IL-4)
cytokines was dramatically impaired after topical
FK506 treatment. Flow cytometric analysis showed that topical
FK506 decreased the population of epidermis-infiltrating CD4+ T cells and suppressed the expression of CD54 and CD80 on I-A+ EC and LNC during
hapten-induced
contact hypersensitivity. Furthermore, topical
FK506 profoundly impaired
oxazolone-induced up-regulation of CD25 expression on CD4+ LNC and dramatically decreased
hapten-induced expansion of I-A+/B220+ and I-A+/CD69+ LNC subsets. In conclusion, these results give new insights into the mechanisms of action of topical
FK506 treatment.