title: Persistent release of IL-1s from skin is associated with systemic cardio-vascular disease, emaciation and systemic amyloidosis: the potential of anti-IL-1 therapy for systemic inflammatory diseases.
abstract: The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.
authors.affiliation: Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Tsu, Mie, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Clinical Engineering, Suzuka University of Medical Science, Suzuka, Mie, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Maruyama
authors.affiliation: Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Isoda
authors.affiliation: Anesthesiology and Critical Care Medicine, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Yokochi
authors.affiliation: Pathology and Matrix Biology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.affiliation: Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Tsuda
authors.affiliation: Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kakeda
authors.affiliation: Cardiology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Okamoto
authors.affiliation: Cardiology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujita
authors.affiliation: Division of Experimental Animal Immunology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Tsu, Mie, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Cardiology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Anesthesiology and Critical Care Medicine, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Immunology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Gabazza
authors.affiliation: Pathology and Matrix Biology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan.
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Molecular Pathology and Cell Adhesion Biology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.affiliation: Department of Dermatology, Mie University, Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Mizutani
mesh_terms: D000686:Amyloidosis / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000276:immunology*; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D004614:Emaciation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012867:Skin / Q000276:immunology / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy*; D014057:Tomography, X-Ray Computed
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D007375:Interleukin-1; D002784:Cholesterol