Involvement of IL-17F via the induction of IL-6 in psoriasis.
Recently, the important role of T helper 17 (Th17) cells in psoriasis has been clarified; however, the role of IL-17F produced by Th17 cells is still not fully understood. IL-6 exhibits multiple biologic functions, such as regulation of immunological responses including those in psoriatic reactions. Therefore, we examined the production of IL-6 protein in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, TNF-alpha, IL-17A, and IL-17A in combination with TNF-alpha, and PBS control. We then examined the expression of IL-6 mRNA in mouse skin after intradermal injection of IL-17F. Finally, IL-17F expression in skin biopsy specimens from psoriasis patients was examined by immunohistochemistry. The results showed that IL-17F induced production of IL-6 in NHEKs in a time-dependent manner. This could be attenuated by chimeric inhibitor blocking the IL-17 receptor. The amounts of IL-6 stimulated by IL-17F were much higher than those stimulated by TNF-alpha or IL-17A. IL-6 was also significantly upregulated via synergistic stimulation with IL-17A plus TNF-alpha. The expression of IL-6 mRNA 24 h after IL-17F injection in the mouse skin was 3.2-fold higher than that in the control group. Immunohistochemistry of inflammatory cells in the dermis demonstrated a large number of CD4(+) T cells showing IL-17F positivity in psoriatic skin lesions, but few or none in non-lesional psoriatic skin. Our results indicate that IL-17F produced by CD4(+) T cells causes the inflammation in psoriasis partly through induction of IL-6 in keratinocytes.
Department of Dermatology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan.
Sawa
S
Fujishima
Hideaki
H
Watanabe
Mio
M
Kawaguchi
Takao
T
Suzuki
Satoshi
S
Matsukura
Tetsuya
T
Homma
Brandon G
BG
Howell
Nobuyuki
N
Hizawa
Toshiyuki
T
Mitsuya
Shau-Ku
SK
Huang
Masafumi
M
Iijima
D000818:Animals; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000473:pathology
C491673:Il17ra protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D053722:Receptors, Interleukin-17; D011993:Recombinant Fusion Proteins