Kagari Takashi, Tanaka Daisuke, Doi Hiromi, Iwakura Yoichiro, Shimozato Takaichi
Biological Research Laboratories, Daiichi Sankyo Co Ltd, Tokyo, Japan.
Eur J Immunol. 2007 Oct;37(10):2753-63. doi: 10.1002/eji.200737313.
Arthritis can be induced in mice by the injection of anti-type II collagen (anti-CII) Ab and LPS. To elucidate the role of IL-1 receptor antagonist (IL-1ra) in Ab-induced arthritis, WT and IL-1ra(-/-) mice were administered anti-CII Ab and LPS. These IL-1ra(-/-) mice developed severe arthritis even at low doses of anti-CII Ab and LPS, while WT mice did not. The cells that invaded the arthritic joints were mainly Gr-1(+) neutrophils, and the number of the cells in the joints remained high over 4 weeks in the IL-1ra(-/-) mice. KC, a ligand for CXCR2, is found in higher levels in the arthritic paws of IL-1ra(-/-) mice compared with the WT, and most of the cells that infiltrated into the joints of the IL-1ra(-/-) mice were CXCR2-expressing neutrophils. Administration of anti-CXCR2 Ab completely inhibited arthritis development. The anti-CXCR2 Ab decreased the number of neutrophils in the blood and also inhibited the migration of neutrophils to KC. These results suggested that the high susceptibility of IL-1ra(-/-) mice to anti-CII Ab-induced arthritis was due to the higher expression of chemotactic factors like KC and the sustained infiltration of CXCR2-expressing neutrophils into the joints.
通过注射抗II型胶原蛋白（抗CII）抗体和脂多糖（LPS）可在小鼠中诱发关节炎。为了阐明白细胞介素-1受体拮抗剂（IL-1ra）在抗体诱导的关节炎中的作用，给野生型（WT）小鼠和IL-1ra基因敲除（IL-1ra(-/-)）小鼠注射抗CII抗体和LPS。这些IL-1ra(-/-)小鼠即使在低剂量的抗CII抗体和LPS作用下也会发展为严重的关节炎，而野生型小鼠则不会。侵入关节炎关节的细胞主要是Gr-1(+)中性粒细胞，并且在IL-1ra(-/-)小鼠中，关节内的细胞数量在4周内一直居高不下。与野生型相比，在IL-1ra(-/-)小鼠的关节炎爪子中，CXCR2的配体角质形成细胞趋化因子（KC）水平更高，并且侵入IL-1ra(-/-)小鼠关节的大多数细胞是表达CXCR2的中性粒细胞。给予抗CXCR2抗体可完全抑制关节炎的发展。抗CXCR2抗体减少了血液中的中性粒细胞数量，也抑制了中性粒细胞向KC的迁移。这些结果表明，IL-1ra(-/-)小鼠对抗CII抗体诱导的关节炎高度敏感是由于趋化因子如KC的表达较高以及表达CXCR2的中性粒细胞持续浸润到关节中。
