From Exploring the Function of IFI27 to Developing an Anti-Psoriatic Therapy Using Topical IFI27 siRNA

Psoriasis is a multifactorial hyperproliferative inflammatory skin disease characterized by hyperproliferation of keratinocytes, aberrant epidermal differentiation, and infiltration of inflammatory cells. In recent years, most research has focused on immunopathogenesis; however, interest in the role of keratinocytes has also been renewed. Furthermore, current topical treatments preferentially targeting keratinocytes are based on antiproliferative or differentiation-modifying activity, or a combination of these actions. Therefore, drugs that normalize the proliferation and differentiation of epidermal keratinocytes still make up a large part of anti-psoriatic therapy. IFI27, belonged to a family of small interferon-alpha (IFN-α)-inducible genes, was first reported over-expressed in breast carcinoma in 1993, and following studies also demonstrated the significant increase of IFI27 expression in psoriasis and certain epithelial cancers. Although it is highly speculated that IFI27 might be a marker for the proliferation of skin keratinocytes, however, the function of IFI27 has not yet been fully investigated. Our preliminary data showed that the IFI27 expression of epidermal keratinocytes could be induced time- and dose-dependently by EGF and TNF-α, two major factors found to be significantly increased in psoriatic patient. The knockdown of IFI27 protein in epidermal keratinocytes resulted in reduced proliferation rate and S-phase arrest, supporting the proliferation-related function of IFI27. The decreased proliferation rate of IFI27 knock-downed keratinocytes might be mediated through p53-p21 signaling pathway which was not associated with the induction of cell apoptosis. IFI27 protein itself was found to be expressed in all phases of cell cycle in keratinocytes. Therefore, it is likely that IFI27 might interact with other proteins to progress the cell cycle particularly the exit from S phase to G2 phase. Over-expression of IFI27 in keratinocytes, on the other hand, accelerated the cell proliferation rate, further confirming the function of IFI27 was involved tightly with the proliferation of keratinocytes. Together, these preliminary data strongly indicate the proliferating role of IFI27 in keratinocytes and the functions of IFI27 might play an important role in the pathogenesis of psoriasis. The present study aims to further investigate the regulatory mechanisms and functions of IFI27 in the first two years and the efficacy of topically administrated IFI27-specific RNAi strategy will be tested in an imiquimod-induced psoriasis-like mice model in the third year. The results of this research project will help us further understand the functions of IFI27 in keratinocytes and IFI27 might be a suitable target for the development of a novel anti-psoriasis therapy.

Project ID:PC10207-0347
External Project ID:NSC102-2314-B182-017