Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype.
Amphiregulin (AR) is a heparin-binding, heparin-inhibited member of the epidermal growth factor (EGF) family and an autocrine growth factor for human keratinocytes. Previous studies have shown that AR expression is increased in psoriatic epidermis. To test the hypothesis that aberrant AR expression is central to the development of psoriatic lesions, we constructed a transgene (K14-ARGE) encoding a human keratin 14 promoter-driven AR gene. Our results indicate that transgene integration and subsequent expression of AR in basal keratinocytes correlated with a psoriasis-like skin phenotype. Afflicted mice demonstrated shortened life spans, prominent scaling and erythematous skin with alopecia, and occasional papillomatous epidermal growths. Histologic examination revealed extensive areas of marked hyperkeratosis with focal parakeratosis, acanthosis, dermal and epidermal lymphocytic and neutrophilic infiltration, and dilated blood vessels within the papillary dermis. Our results reveal that AR exerts activity in the skin that is distinct from that of transgenic transforming growth factor-alpha or other cytokines, and induces skin pathology with striking similarities to psoriasis. Our observations also link the keratinocyte EGF receptor-ligand system to psoriatic inflammation, and suggest that aberrant expression of AR in the epidermis may represent a critical step in the development or propagation of psoriatic lesions.
Cook
P W
PW
Department of Dermatology, The Oregon Health Sciences University, Portland 97201, USA. cookp@ohsu.edu
Piepkorn
M
M
Clegg
C H
CH
Plowman
G D
GD
DeMay
J M
JM
Brown
J R
JR
Pittelkow
M R
MR
D066258:Amphiregulin; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D066255:EGF Family of Proteins; D004817:Epidermis / Q000502:physiology; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics*; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007633:Keratins / Q000235:genetics; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011565:Psoriasis / Q000235:genetics* / Q000473:pathology
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D017252:CD3 Complex; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D007633:Keratins