TNF-α induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A2 activation

Il Whan Choi, Sun-Kim, Young Suk Kim, Hyun Mi Ko, Suhn Young Im, Jae Hong Kim, Hye Jin You, Yong Chul Lee, Jae Hoon Lee, Young Min Park, Hern Ku Lee

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Background: Late-phase airway hyperresponsiveness (AHR) in asthma is considered the event leading to persistent inflammation in the lungs, but the molecular mechanisms involved in this process are poorly understood. Objective: To examine the role of TNF-α in the development of a late AHR and airway inflammation in asthma. Methods: We established a murine model of asthma with not only biphasic AHR to methacholine but also airway eosinophilia. The effect of TNF-α blockade was determined by using anti-TNF-α antibody and TNF-α knockout mice. Cytosolic phospholipase A2 (cPLA 2) mRNA expression and activity were assessed by using RT-PCR and 1-stearoyl-2-[1-14C] arachidonyl-sn-glycero-3-phosphocholine as the substrate, respectively. Results: TNF-α blockade resulted in significant inhibition of the late AHR without affecting the early AHR, and reduction in airway eosinophilia and inflammation. cPLA2 activity was increased in asthmatic lungs in a TNF-α-dependent way, and cPLA2 inhibitor blocked late AHR and airway eosinophilia. TNF-α also stimulated the synthesis of cPLA2 metabolites such as leukotriene B4 and platelet-activating factor in the airway. Specific inhibitors of cPLA 2 metabolites inhibited the late AHR and airway eosinophilia. Conclusions: TNF-α is the proximal key cytokine capable of developing late-phase AHR and subsequent airway inflammation through expression/activation of cPLA2.

Original languageEnglish
Pages (from-to)537-543
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume116
Issue number3
DOIs
Publication statusPublished - 2005 Sep

Keywords

  • 5-lipoxygenase
  • Airway inflammation
  • Asthma
  • Cyclooxygenase
  • Cytosolic phospholipase A
  • Late airway response
  • Platelet-activating factor
  • TNF-α

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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