Kinin B-1 receptor up-regulation after lipopolysaccharide administration: Role of proinflammatory cytokines and neutrophil influx

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Passos, Giselle F.
Fernandes, Elizabeth S.
Campos, Maria M.
Araujo, José GVC
Pesquero, Jorge L.
Souza, Glória EP
Avellar, Maria CW [UNIFESP]
Teixeira, Mauro M.
Calixto, João B.
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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.
Journal Of Immunology. Bethesda: Amer Assoc Immunologists, v. 172, n. 3, p. 1839-1847, 2004.