Reimers J, Wogensen L D, Welinder B, Hejnaes K R, Poulsen S S, Nilsson P, Nerup J
Steno Memorial and Hvidøre Hospital, Gentofte, Denmark.
Scand J Immunol. 1991 Nov;34(5):597-610. doi: 10.1111/j.1365-3083.1991.tb01583.x.
Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from the circulation with a T1/2 alpha of 2.9 min and a T1/2 beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated that 125I-rIL-1 beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact 125I-rIL-1 beta were found in the circulation after i.v., intraperitoneal (i.p.) and subcutaneous (s.c.) injections, as demonstrated by high performance size exclusion chromatography, trichloracetic acid precipitation and SDS-PAGE until 5 h after tracer injection. Pre-treatment with 'cold' rIL-1 beta enhanced degradation of a subsequent injection of tracer. The route of administration was of importance for the biological effects of rIL-1 beta, as demonstrated by a reduced food intake, increased rectal temperature and blood glucose after s.c. injection of rIL-1 beta compared with i.p. The present demonstration of intact rIL-1 beta in the circulation and the islets of Langerhans supports the hypothesis that systemic IL-1 beta may be involved in the initial beta-cell destruction leading to IDDM in humans.
基于大鼠体内实验，最近有人提出，循环中的白细胞介素1可能参与导致人类胰岛素依赖型糖尿病（IDDM）的β细胞破坏的初始事件。本研究的目的是通过单标记、具有生物活性的125I-rIL-1β来估计重组人白细胞介素1β（rIL-1β）的分布半衰期（T1/2α）和消除半衰期（T1/2β），及其组织分布和细胞定位。静脉注射后，125I-rIL-1β从循环中消除，T1/2α为2.9分钟，T1/2β为41.1分钟。中央和外周分布容积分别为20.7和19.1 ml/大鼠，代谢清除率为16.9 ml/分钟/千克。肾脏和肝脏显示出最高的示踪剂积累，放射自显影表明125I-rIL-1β定位于肾脏的近端小管和肝脏的肝细胞。此外，颗粒定位于胰腺的胰岛。静脉注射、腹腔注射和皮下注射后，通过高效尺寸排阻色谱、三氯乙酸沉淀和SDS-PAGE证明，循环中存在与完整的125I-rIL-1β相对应的示踪剂结合蛋白，直到示踪剂注射后5小时。用“冷”rIL-1β预处理可增强随后注射的示踪剂的降解。给药途径对rIL-1β的生物学效应很重要，与腹腔注射相比，皮下注射rIL-1β后食物摄入量减少、直肠温度升高和血糖升高证明了这一点。目前在循环和胰岛中存在完整rIL-1β的证明支持了全身性IL-1β可能参与导致人类IDDM的初始β细胞破坏的假说。
