Analysis of the roles of IL-1 on homeostasis using mice deficient for negative regulators of IL-1 signaling
Shunta Sakanishi1, Shigeru Kakuta1, 2, Kenji Shimizu2, 3, Aoi Akitsu2, 3, Takashi Matsuwaki4, James Ken Chambers5, Kaito Masaki6, Sachiko Kubo2, 4, Yang Liu2, Akiko Nakajima2, Reiko Horai2, 7, Harumichi Ishigame2, 8, Seiji Takashima6, Yoichiro Iwakura2, 4, Shigeru Kyuwa1
1Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan, 2Center for Experimental Medicine and Systems Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan, 3Center for Experimental Animal Models, Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan, 4Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan, 5Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan, 6Faculty of Textile Science and Technology, Shinshu University, Ueda, Japan, 7Laboratory of Immunology, National Eye Institute, NIH, Bethesda, United States, 8Laboratory of Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
IL-1 plays an important role on homeostasis in several tissues. IL-1 signaling is negatively regulated by two different type molecules, receptor antagonist (Ra) and type 2 receptor (R2). In addition, IL-1Ra consists some isoforms encoded by specific 1st exon and shared 3’ exons. However, details of in vivo function of these negative regulators still have been unknown. In this study, mice combinational deficient for IL-1R2 and 3 types of IL-1Ra (full or isoform specific mutations) were generated in C57BL/6 background and characterized. Mice single deficient for IL-1Ra or IL-1R2 showed mild phenotypes. In contrast, IL-1R2 and IL-1Rafull double deficient mice showed severe tail dermatitis and growth restriction. Body weight gain plateaued at 5 weeks old in the double deficient mice. These severe phenotypes were not observed in IL-1R2 and isoform-specific IL-1Ra double deficiency. These results suggest that IL-1 signaling is negatively regulated by both IL-1R2 and all IL-1Ra isoforms, and IL-1R2 and IL-1Rafull double deficient mice are useful tools for analysis of IL-1 function in vivo.