Functional expression of heme oxygenase-1 in human differentiated epidermis and its regulation by cytokines.
Although heme oxygenase-1 (HO-1) is induced in keratinocytes after UV radiation, HO-1 expression during normal epidermal differentiation has not yet been reported. We showed by real-time PCR, western blotting, and ELISA that HO-1 mRNA and protein expression by cultured normal human keratinocytes was upregulated during epidermal differentiation induced by a high-calcium medium. Immunohistochemical staining and in situ hybridization showed the graduated expression of HO-1 in the upper epidermis, which was accompanied by suprabasal HO-1 mRNA expression, and the accumulation of bilirubin (BR) in the stratum corneum. We examined the activation of nuclear factor E2-related factor 2 (Nrf2), which is a pivotal transcription factor for HO-1 expression, by western blotting and by examining the mRNA expression of Nrf2 target genes, and excluded its role in HO-1 expression in epidermal differentiation. Next, we examined the regulation of HO-1 expression by inflammatory cytokines. IL-4 and IL-22 significantly reduced HO-1 mRNA and protein expression, whereas IL-1beta, IL-17A, and tumor necrosis factor-alpha (TNF-alpha) increased it. Finally, immunohistochemical studies on psoriatic lesional skin showed that HO-1 expression was downregulated in the parakeratotic epidermis, whereas it was retained in the orthokeratotic epidermis. These studies demonstrate that HO-1 is functionally expressed by keratinocytes in parallel with epidermal differentiation and that its expression is independently affected by several cytokines.
Numata
Ikuko
I
Department of Dermatology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan.
Okuyama
Ryuhei
R
Memezawa
Ai
A
Ito
Yumiko
Y
Takeda
Kazuhisa
K
Furuyama
Kazumichi
K
Shibahara
Shigeki
S
Aiba
Setsuya
S
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000276:immunology; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; C508717:IL17A protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1