Expression of antiapoptotic protein c-FLIP is upregulated in psoriasis epidermis

Abstract

The most characteristic change in psoriasis is markedly increased, persistent keratinocyte proliferation. The pathogenic mechanism underlying the hyperproliferation of keratinocytes in psoriasis is still not completely clarified. Cellular FLIP (cFLIP) is a close homologue of caspase 8 without the caspase activity that inhibits Fas signaling. The cFLIP protein is often expressed in human tumors and is believed to suppress antitumor immune responses involving the Fas system. PCNA is an auxiliary protein of DNA polymerase-5, which appears early in G1 and becomes more abundant in the S phase, thereafter declining during G2/M phases of the cell cycle. Thus, the PCNA staining profiles were used as markers of keratinocyte proliferation. Our objective was to obtain insight into the role of c-FLIP in kerarinocyte proliferation and to investigate further the pathogenesis of psoriasis. Using real time quantitative reverse transcriptase-polymerase chain reactions (RT-PCR) and immunohistochemical staining, we studied the expression of c-FLIP mRNA and protein in skin biopsies from psoriatic patients and healthy subjects. Apoptotic cells were evaluated using the terminal deoxynucleotide transferase (TdT) mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. c-FLIP mRNA and protein expressions were significantly greater in lesional psoriatic epidermis compared with normal and non-lesional psoriatic epidermis (P < 0.01). c-FLIP was strongly expressed within all epidermal layers in lesional psoriatic skin, whereas weak c-FLIP staining was restricted to the basal and suprabasal layers in normal and non-lesional psoriatic epidermis. c-FLIP protein levels significantly correlated with PASI score, PCNA and apoptosis index (Spearman's rho = 0.83; rho = 0.61; rho = - 0.41; P < 0.05, respectively). We conclude that over-expression of c-FLIP in lesional psoriatic skin might contribute to abnormal keratinocyte proliferation due to a functional decrease in the apoptotic pathway.