title: Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands.
abstract: To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5' and 3' untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5-fold increase in Ki-67(+) cells) accompanied by significantly increased CD4+ T-cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG-UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67(+) cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Stoll
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Sahil
authors.initials: S
authors.lastname: Sekhon
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Talsma
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Maya I
authors.initials: MI
authors.lastname: Camhi
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Jones
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Lambert
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Hue
authors.initials: H
authors.lastname: Marley
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Rittié
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Grachtchouk
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.|Ann Arbor VA Hospital, Ann Arbor, MI, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D066258:Amphiregulin / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D004817:Epidermis / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D007249:Inflammation; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012627:Sebaceous Glands / Q000378:metabolism; D012867:Skin / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; C587848:AREG protein, human; D066258:Amphiregulin; D008024:Ligands; D066246:ErbB Receptors
keywords: EGF receptor; amphiregulin; psoriasis; sebaceous glands; skin inflammation