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*
Department of Dermatology, University of Dusseldorf, Dusseldorf, Germany;
Department of Dermatology, University of Helsinki, Helsinki, Finland; and
Department of Dermatology, Institute of Toxicology, Bayer AG, Wuppertal, Germany
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-1
, IL-1ß, IL-2, IL-4, IL-12 p35, IL-12 p40,
macrophage inflammatory protein-2 (MIP-2), granulocyte-macrophage CSF
(GM-CSF), TNF-, and IFN-
) 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-1, IL-1ß, GM-CSF, TNF-,
MIP-2, and IFN- in EC and for IL-2, IL-4, IL-12 p35, IL-12 p40, and
IFN- 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-1,
IL-1ß, GM-CSF, TNF-, MIP-2, and IFN- 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 Th1 (IFN- 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.
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