Matsukawa A, Hogaboam C M, Lukacs N W, Lincoln P M, Evanoff H L, Strieter R M, Kunkel S L
Departments ofPathology and Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2000 Mar 1;164(5):2738-44. doi: 10.4049/jimmunol.164.5.2738.
IL-13 has been shown to exert potent anti-inflammatory properties. In this study, we elucidated the functional role of endogenous IL-13 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies demonstrated that the level of IL-13 increased in tissues including liver, lung, and kidney, whereas no considerable increase was found in either peritoneal fluid or serum after CLP. Immunohistochemically, IL-13-positive cells were Kupffer cells in liver, alveolar macrophages in lung, and epithelial cells of urinary tubules in kidney. IL-13 blockade with anti-IL-13 Abs significantly decreased the survival rate of mice after CLP from 53% to 14% on day 7 compared with control. To determine the potential mechanisms whereby IL-13 exerted a protective role in this model, the effects of anti-IL-13 Abs on both local and systemic inflammation were investigated. Administration of anti-IL-13 Abs did not alter the leukocyte infiltration and bacterial load in the peritoneum after CLP but dramatically increased the neutrophil influx in tissues after CLP, an effect that was accompanied by significant increases in the serum levels of aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine. Tissue injury caused by IL-13 blockade was associated with increases in mRNA and the protein levels of CXC chemokines macrophage inflammatory protein-2 and KC as well as the CC chemokine macrophage inflammatory protein-1alpha and the proinflammatory cytokine TNF-alpha. Collectively, these results suggest that endogenous IL-13 protected mice from CLP-induced lethality by modulating inflammatory responses via suppression of overzealous production of inflammatory cytokines/chemokines in tissues.
白细胞介素-13（IL-13）已被证明具有强大的抗炎特性。在本研究中，我们阐明了内源性IL-13在盲肠结扎和穿刺（CLP）诱导的脓毒症性腹膜炎小鼠模型中的功能作用。初步研究表明，包括肝脏、肺和肾脏在内的组织中IL-13水平升高，而CLP后腹膜液或血清中未发现明显升高。免疫组织化学显示，肝脏中的枯否细胞、肺中的肺泡巨噬细胞和肾脏肾小管上皮细胞为IL-13阳性细胞。与对照组相比，用抗IL-13抗体阻断IL-13可使CLP后小鼠在第7天的存活率从53%显著降低至14%。为了确定IL-13在该模型中发挥保护作用的潜在机制，研究了抗IL-13抗体对局部和全身炎症的影响。给予抗IL-13抗体并未改变CLP后腹膜中的白细胞浸润和细菌载量，但显著增加了CLP后组织中的中性粒细胞流入，这一效应伴随着血清中天冬氨酸转氨酶、丙氨酸转氨酶、血尿素氮和肌酐水平的显著升高。IL-13阻断引起的组织损伤与CXC趋化因子巨噬细胞炎性蛋白-2和KC以及CC趋化因子巨噬细胞炎性蛋白-1α和促炎细胞因子肿瘤坏死因子-α的mRNA和蛋白质水平升高有关。总体而言，这些结果表明，内源性IL-13通过抑制组织中炎性细胞因子/趋化因子的过度产生来调节炎症反应，从而保护小鼠免受CLP诱导的致死性。
