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

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91 Citations (Scopus)


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
Issue number3
Publication statusPublished - 2005 Sept

Bibliographical note

Funding Information:
Supported by the Korea Science and Engineering Foundation through the Research Center for Allergic Immune Diseases at Chonbuk National University Medical School and by grant the National Research Laboratory Program, Korea Science and Engineering Foundation (Dr Y-C Lee).


  • 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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