Krupa Agnieszka, Kato Hiroyuki, Matthay Michael A, Kurdowska Anna K
Department of Biochemistry, University of Texas Health Center, 11937 US Highway 271, Tyler, TX 75708-3154, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1105-13. doi: 10.1152/ajplung.00277.2003. Epub 2004 Jan 16.
A significant fraction of IL-8 in lung fluids from patients with the acute lung injury (ALI) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes), and lung fluid concentrations of these complexes correlate with development and outcome of ALI. In this study, we examined whether anti-IL-8:IL-8 complexes exhibit proinflammatory activity in vitro. These complexes were purified from pulmonary edema fluid samples obtained from patients with ALI. First, we found that IL-8 bound to the autoantibody retained its ability to trigger chemotaxis of neutrophils, whereas control antibody did not have significant chemotactic activity. Next, we examined the ability of anti-IL-8:IL-8 complexes to induce neutrophil activation, i.e., neutrophil respiratory burst and degranulation. Anti-IL-8:IL-8 complexes triggered superoxide and myeloperoxidase release from human neutrophils, and in contrast, the control antibody had no effect. We also demonstrated that IgG receptor, FcgammaRIIa, is the receptor involved in cellular activation mediated by these complexes. Blockade of FcgammaRIIa completely reverses activity of the complexes with the exception of chemotaxis. Both FcgammaRIIa and IL-8 receptors mediate chemotactic activity of anti-IL-8:IL-8 complexes, with FcgammaRIIa being, however, a predominant receptor. Furthermore, activity of the complexes is partially dependent on the activation of the mitogen-activated protein kinases, i.e., ERK and p38, important components of the FcgammaRIIa signaling cascade. Anti-IL-8:IL-8 complexes may therefore be involved in the pathogenesis of lung inflammation in clinical acute lung injury.
急性肺损伤（ALI）患者肺液中相当一部分白细胞介素-8（IL-8）与抗IL-8自身抗体（抗IL-8：IL-8复合物）相关，这些复合物的肺液浓度与ALI的发生发展及预后相关。在本研究中，我们检测了抗IL-8：IL-8复合物在体外是否具有促炎活性。这些复合物从ALI患者的肺水肿液样本中纯化得到。首先，我们发现与自身抗体结合的IL-8保留了触发中性粒细胞趋化性的能力，而对照抗体则没有显著的趋化活性。接下来，我们检测了抗IL-8：IL-8复合物诱导中性粒细胞活化的能力，即中性粒细胞呼吸爆发和脱颗粒。抗IL-8：IL-8复合物触发了人中性粒细胞中超氧化物和髓过氧化物酶的释放，相比之下，对照抗体则没有作用。我们还证明，IgG受体FcγRIIa是参与这些复合物介导的细胞活化的受体。阻断FcγRIIa除了趋化性外，完全逆转了复合物的活性。FcγRIIa和IL-8受体都介导抗IL-8：IL-8复合物的趋化活性，然而，FcγRIIa是主要受体。此外，复合物的活性部分依赖于丝裂原活化蛋白激酶即ERK和p38的激活，它们是FcγRIIa信号级联的重要组成部分。因此，抗IL-8：IL-8复合物可能参与了临床急性肺损伤中肺部炎症的发病机制。
