FK506 independently upregulates transforming growth factor beta and downregulates inducible nitric oxide synthase in cultured human keratinocytes: possible mechanisms of how tacrolimus ointment interacts with atopic skin

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Abstract
Tacrolimus ointment (FK506) has been used in recent years for the treatment of atopic dermatitis (AD), with favourable results. Most of the therapeutic efficacy of FK506 in AD has been attributed to its immunomodulatory effects on different immune cell types, but its effects on keratinocytes (KCs) have rarely been discussed. Studies have shown that low expression of transforming growth factor (TGF)-beta and high expression of nitric oxide synthase (NOS) are implicated in the pathogenesis of AD. To investigate the direct effects of FK506 on KCs in terms of TGF-beta and inducible NOS (iNOS), and to explore the interactions between TGF-beta and iNOS in the KC system. Cultured human KCs treated with different concentrations of FK506 were used for investigation. The changes in the KC system induced by FK506 were documented in terms of TGF-beta and iNOS using enzyme-linked immunosorbent assay and Western blotting techniques, respectively. The gene expression of both TGF-beta and iNOS was also determined. A certain amount of tumour necrosis factor (TNF)-alpha was introduced to mimic atopic skin in vivo. Our results showed that the release of TGF-beta was upregulated in FK506-treated KCs, particularly in the presence of TNF-alpha, while the expression of iNOS was downregulated. The gene expression of iNOS was also downregulated, as shown by reverse transcriptase-polymerase chain reaction analysis. However, the addition of TNF-alpha did not further downregulate the expression of iNOS protein, suggesting that FK506 may regulate TGF-beta and iNOS through different pathways. Our findings indicate that the direct effects of FK506 on KCs probably contribute to its therapeutic efficacy in the treatment of AD.

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