Passos Giselle F, Fernandes Elizabeth S, Campos Maria M, Araújo José G V C, Pesquero Jorge L, Souza Glória E P, Avellar Maria C W, Teixeira Mauro M, Calixto João B
Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
J Immunol. 2004 Feb 1;172(3):1839-47. doi: 10.4049/jimmunol.172.3.1839.
Several studies have now clearly established the ability of LPS to induce bradykinin B(1) receptor up-regulation in vivo and the functional relevance of this up-regulation for the pathophysiological effects of LPS. Using an in vivo system in which LPS is injected locally into the rat paw, we have examined the potential contribution of proinflammatory cytokines, NF-kappaB activation, and neutrophil influx for the functional and molecular up-regulation of the bradykinin B(1) receptor. Treatment with LPS resulted in a rapid and sustained functional up-regulation of B(1) receptors in the rat paw that correlated with the increase in B(1) receptor mRNA levels. B(1) receptor up-regulation is preceded by the rapid activation of the transcription factor NF-kappaB and the production of proinflammatory cytokines, including TNF-alpha and IL-1beta. More importantly, blockade of NF-kappaB translocation, TNF-alpha, or IL-1beta prevented the functional and molecular up-regulation of B(1) receptors. Injection of LPS also induced the influx of neutrophils that followed the peak of cytokine production and associated with the persistent activation of NF-kappaB and functional B(1) receptor up-regulation. Blockade of neutrophil influx with platelet-activating factor receptor antagonists or cell adhesion molecule blockers prevented B(1) receptor up-regulation. Thus, by acting in cooperation and in a coordinated, timely manner, TNF-alpha, IL-1beta, neutrophils, and the transcription factor NF-kappaB are major and essential players in the ability of LPS to induce B(1) receptor expression in vivo.
现在有几项研究已经明确证实了脂多糖（LPS）在体内诱导缓激肽B（1）受体上调的能力，以及这种上调对于LPS病理生理效应的功能相关性。利用将LPS局部注射到大鼠爪中的体内系统，我们研究了促炎细胞因子、核因子κB（NF-κB）激活和中性粒细胞流入对缓激肽B（1）受体功能和分子上调的潜在作用。用LPS处理导致大鼠爪中B（1）受体快速且持续的功能上调，这与B（1）受体mRNA水平的增加相关。B（1）受体上调之前是转录因子NF-κB的快速激活以及促炎细胞因子的产生，包括肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）。更重要的是，阻断NF-κB易位、TNF-α或IL-1β可防止B（1）受体的功能和分子上调。注射LPS还诱导中性粒细胞流入，其跟随细胞因子产生的峰值，并与NF-κB的持续激活和功能性B（1）受体上调相关。用血小板活化因子受体拮抗剂或细胞粘附分子阻滞剂阻断中性粒细胞流入可防止B（1）受体上调。因此，通过协同且协调、及时地发挥作用，TNF-α、IL-1β、中性粒细胞和转录因子NF-κB是LPS在体内诱导B（1）受体表达能力中的主要且关键因素。
