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Cytochrome P450 4Fs as a novel target in treatment of inflammatory skin disease
Author(s) -
Kalsotra Auinash,
Du Luping,
Wang Ying,
Keeney Diane S,
Strobel Henry W
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a85-e
Subject(s) - retinoic acid , inflammation , psoriasis , hacat , leukotriene b4 , keratinocyte , proinflammatory cytokine , arachidonic acid , immunology , retinoid , chemistry , tretinoin , chemotaxis , receptor , biology , pharmacology , microbiology and biotechnology , biochemistry , in vitro , enzyme , gene
Cytochrome P450 (CYP) 4Fs are novel proteins in the P450 superfamily that metabolize eicosanoids such as leukotriene B 4 (LTB 4 ) and other inflammatory lipid mediators in the arachidonic acid cascade. These inactive hydroxy products are incapable of chemotaxis and recruitment of immune cells to the sites of inflammation. In this study, we show that CYP4Fs are highly expressed in differentiating keratinocytes in the human skin. We have discovered that primary keratinocytes when differentiated in‐vitro produce up to a 150 fold induction of CYP4F mRNA. Treatment with retinoic acid inhibits keratinocyte differentiation but causes CYP4F upregulation. This induction is translated into active protein which leads to enhanced rate of LTB 4 breakdown. The molecular mechanism of CYP4F induction by retinoic acid is mediated through Retinoic X Receptors. Furthermore we show that in inflammatory skin diseases like Psoriasis, there is aberrant differentiation of keratinocytes and that the CYP4F levels in psoriatic skin are much higher than normal skin. Retinoic acid therapy is considered as a novel treatment of inflammatory skin diseases like psoriasis. Although it is known that retinoic acid inhibits skin differentiation but their mechanism of resolving skin inflammation is not understood. Here we provide mechanistic details of retinoic acid treatment in curtailing skin inflammation through induction of CYP4Fs which inactivate proinflammatory eicosanoids. The loss of pro‐inflammatory eicosanoids in psoriatic lesions decreases the chemotactic response of leukocytes and T‐cells at these sites leading to restoration of normal skin.