-Original-

Interleukin-1beta Inhibition Attenuates Vasculitis in a Mouse Model of Kawasaki Disease

Yoshiaki Hashimoto¹, Ryuji Fukazawa¹, Noriko Nagi-Miura², Naohito Ohno², Nobuko Suzuki¹, Yasuhiro Katsube¹, Mitsuhiro Kamisago¹, Miharu Akao¹, Makoto Watanabe¹, Koji Hashimoto¹, Kanae Tsuno¹, Ryosuke Matsui¹ and Yasuhiko Itoh¹

¹Department of Pediatrics, Nippon Medical School
²Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Sciences

Background: Kawasaki disease (KD), a systemic vasculitis, is suspected to be related to abnormalities in innate immunity. Based on the important role of IL-1 signaling in innate immunity, we investigated the effects of an anti-IL-1β antibody using a Candida albicans water-soluble fraction (CAWS)-induced mouse model of KD.
Methods: CAWS (0.5 mg/mouse) was injected intraperitoneally into 5-week-old DBA/2 mice on five consecutive days. An anti-Murine IL-1β antibody (01BSUR) was administered at various doses (2.5, 5.0, and 10.0 mg/kg) and time points (2 days before, same day, and 2, 5, 7, and 14 days after CAWS administration). After 4 weeks, vasculitis in the aortic root was investigated histologically. Cytokines including IL-1β, -6, -10, and TNF-α were also measured.
Results: Groups administered 01BSUR at all doses showed a significant reduction in the area of vasculitis. In addition, 01BSUR inhibited vasculitis until 7 days after CAWS administration. In the analysis of various time points, the level of IL-6 was lower in all groups compared to the CAWS only group, but the levels of IL-1β, TNFα, and IL-10 were lower when 01BSUR was administered before CAWS. On the other hand, TNFα and IL-10 levels were restored when 01BSUR was administered after CAWS, suggesting that 01BSUR may have additional effects beyond blocking IL-1β signaling.
Conclusions: The anti-IL-1β antibody significantly attenuated CAWS-induced vasculitis. The mechanism of inhibiting vasculitis is thought to include inhibition of the IL-1β pathway and additional effects beyond blocking IL-1β signaling.

J Nippon Med Sch 2019; 86: 108-116

Keywords
Kawasaki disease, interleukin-1beta, Kawasaki disease model mouse, cytokine profile, interleukin-10

Correspondence to
Ryuji Fukazawa, Department of Pediatrics, Nippon Medical School, 1-1-3 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
oraora@nms.ac.jp

Received, December 6, 2018
Accepted, January 10, 2019