Transepithelial migration of neutrophils in response to leukotriene B4 is mediated by a reactive oxygen species-extracellular signal-regulated kinase-linked cascade

Chang Hoon Woo, Min Hyuk Yoo, Hye Jin You, Sung Hoon Cho, Yeung Chul Mun, Chu Myong Seong, Jae-Hong Kim

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

The epithelial cells that form a barrier lining the lung airway are key regulators of neutrophil trafficking into the airway lumen in a variety of lung inflammatory diseases. Although the lipid mediator leukotriene B4 (LTB4) is known to be a principal chemoattractant for recruiting neutrophils to inflamed sites across the airway epithelium, the precise signaling mechanism involved remains largely unknown. In the present study, therefore, we investigated the signaling pathway through which LTB4 induces transepithelial migration of neutrophils. We found that LTB4 induces concentration-dependent transmigration of DMSO-differentiated HL-60 neutrophils and human polymorphonuclear neutrophils across A549 human lung epithelium. This effect was mediated via specific LTB4 receptors and was inhibited by pretreating the cells with N-acetylcysteine (NAC), an oxygen free radical scavenger, with diphenylene iodonium (DPI), an inhibitor of NADPH oxidase-like flavoproteins, or with PD98059, an extracellular signal-regulated kinase (ERK) inhibitor. Consistent with those findings, LTB4-induced ERK phosphorylation was completely blocked by pretreating cells with NAC or DPI. Taken together, our observations suggest LTB4 signaling to transepithelial migration is mediated via generation of reactive oxygen species, which leads to downstream activation of ERK. The physiological relevance of this signaling pathway was demonstrated in BALB/c mice, in which intratracheal instillation of LTB4 led to acute recruitment of neutrophils into the airway across the lung epithelium. Notably, the response to LTB4 was blocked by NAC, DPI, PD98059, or CP105696, a specific LTB4 receptor antagonist.

Original languageEnglish
Pages (from-to)6273-6279
Number of pages7
JournalJournal of Immunology
Volume170
Issue number12
Publication statusPublished - 2003 Jun 15

ASJC Scopus subject areas

  • Immunology

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