IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions.
Atopic dermatitis (AD) is a pruritic inflammatory skin disease. Because IL-18 directly stimulates T cells and mast cells to release AD-associated molecules, Th2 cytokines, and histamine, we investigated the capacity of IL-18 to induce AD-like inflammatory skin disease by analyzing KIL-18Tg and KCASP1Tg, which skin-specifically overexpress IL-18 and caspase-1, respectively. They spontaneously developed relapsing dermatitis with mastocytosis and Th2 cytokine accumulation accompanied by systemic elevation of IgE and histamine. Stat6-deficient KCASP1Tg displayed undetectable levels of IgE but manifested the same degree of cutaneous changes, whereas IL-18-deficient KCASP1Tg evaded the dermatitis, suggesting that IL-18 causes the skin changes in the absence of IgE/stat6. KIL-18Tg and IL-1-deficient KCASP1Tg took longer to display the lesion than KCASP1Tg. Thus, AD-like inflammation is initiated by overrelease of IL-18 and accelerated by IL-1. Our present study might provide insight into understanding the pathogenesis of and establishing therapeutics for chronic inflammatory skin diseases including AD.
Konishi
Hiroshi
H
Department of Dermatology, Mie University School of Medicine, Tsu 514-8507, Japan.
Tsutsui
Hiroko
H
Murakami
Takaaki
T
Yumikura-Futatsugi
Shizue
S
Yamanaka
Kei-Ichi
K
Tanaka
Minoru
M
Iwakura
Yohichiro
Y
Suzuki
Noboru
N
Takeda
Kiyoshi
K
Akira
Shizuo
S
Nakanishi
Kenji
K
Mizutani
Hitoshi
H
D000818:Animals; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D007249:Inflammation; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011537:Pruritus / Q000235:genetics / Q000276:immunology*; D011817:Rabbits; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000276:immunology*
D020382:Interleukin-18; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007073:Immunoglobulin E; D007633:Keratins