Conti P, Panara M R, Fridas S, Barbacane R C, Grilli A, Placido F C, Reale M, Fiore S
Immunology Division, University of Chieti Medical School, Italy.
Cell Immunol. 1993 Apr 1;147(2):446-57. doi: 10.1006/cimm.1993.1083.
Interleukin-1 (IL-1) is a polypeptide which mediates several systemic changes associated with infection, inflammation and injury, such as fever, neutrophilia, increased acute phase protein synthesis, and arachidonic acid metabolites. Recently, a natural inhibitor of IL-1 has been cloned, called IL-1 receptor antagonist (IL-1ra), which prevents Escherichia coli-induced shock in rabbits and blocks PGE2 induced by IL-1. In this report we study the effect of human recombinant (hr) IL-1ra on chronic inflammation induced by dorsal injections of 200 microliters of a 1:40 saturated crystal solution of potassium permanganate (KMnO4) in mice. After 7 days, all mice developed a subcutaneous granulomatous tissue indicative of a chronic inflammatory response, at the site of injection. KMnO4-treated mice, injected intraperitoneally twice with hrIL-1ra, 20 micrograms/dose (the first at the same time of induction of the granuloma and the second 24 hr later), show significant decreases in size and weight of the granuloma when compared to mice not treated with hrIL-1ra (controls); the inhibitory effect was approximately 32-46 and 25-51%, respectively. In addition, in all mice treated with hrIL-1ra, there was a strong inhibition of PGE2 and LTB4 on assay of freshly minced granuloma tissue. Moreover, when hrIL-1 beta (1.0 ng/ml) or LPS (100 ng/ml) were added overnight to the minced granuloma tissue cultures, these compounds enhanced the production of LTB4 and PGE2 from the untreated mice, whereas in IL-1ra-treated mice they failed. In the histological studies of the granuloma, animals treated with hrIL-1ra show a lesser degree of mononuclear cell (MC) accumulation. The inhibitory effect of hrIL-1ra on PGE2 production was also confirmed on peritoneal macrophages from untreated mice, stimulated overnight with hrIL-1 beta or LPS in vitro. The resulting inhibition was dose-dependent. In these studies we show, for the first time, the anti-inflammatory effect of hrIL-1ra on chronic inflammation as assessed by the inhibition of granuloma formation, PGE2, LTB4, and white cell accumulation in inflamed tissue.
白细胞介素-1（IL-1）是一种多肽，它介导与感染、炎症和损伤相关的多种全身变化，如发热、中性粒细胞增多、急性期蛋白合成增加以及花生四烯酸代谢产物。最近，一种IL-1的天然抑制剂已被克隆出来，称为IL-1受体拮抗剂（IL-1ra），它可预防兔大肠杆菌诱导的休克，并阻断IL-1诱导的PGE2。在本报告中，我们研究了人重组（hr）IL-1ra对小鼠背部注射200微升1:40高锰酸钾（KMnO4）饱和晶体溶液诱导的慢性炎症的影响。7天后，所有小鼠在注射部位都出现了皮下肉芽肿组织，表明存在慢性炎症反应。用hrIL-1ra腹腔注射两次（剂量为20微克/剂，第一次在肉芽肿诱导时，第二次在24小时后）的KMnO4处理小鼠，与未用hrIL-1ra处理的小鼠（对照组）相比，肉芽肿的大小和重量显著减小；抑制作用分别约为32 - 46%和25 - 51%。此外，在用hrIL-1ra处理的所有小鼠中，新鲜切碎的肉芽肿组织检测显示PGE2和LTB4受到强烈抑制。而且，当将hrIL-1β（1.0纳克/毫升）或LPS（100纳克/毫升）过夜添加到切碎的肉芽肿组织培养物中时，这些化合物增强了未处理小鼠LTB4和PGE2的产生，而在IL-1ra处理的小鼠中则没有。在肉芽肿的组织学研究中，用hrIL-1ra处理的动物单核细胞（MC）积累程度较低。hrIL-1ra对PGE2产生的抑制作用在未处理小鼠的腹腔巨噬细胞体外过夜用hrIL-1β或LPS刺激时也得到了证实。产生的抑制作用是剂量依赖性的。在这些研究中，我们首次表明，通过抑制肉芽肿形成、PGE2、LTB4以及炎症组织中白细胞积累来评估，hrIL-1ra对慢性炎症具有抗炎作用。
