Production of interleukin (IL)-33 in the lungs during multiple antigen challenge-induced airway inflammation in mice, and its modulation by a glucocorticoid

Eur J Pharmacol. 2015 Jun 15:757:34-41. doi: 10.1016/j.ejphar.2015.03.015. Epub 2015 Mar 20.


Although interleukin (IL)-33 is a candidate aggravator of asthma, the cellular sources of IL-33 in the lungs during the progression of antigen-induced airway inflammation remain unclear. Furthermore, it has not been determined whether the antigen-induced production of IL-33 can be pharmacologically modulated in vivo. In this study, we examined the production of IL-33 in the lungs of sensitized mice during multiple intratracheal challenges with the antigen, ovalbumin. The 1st challenge clearly induced the IL-33 production in the lungs, and it was enhanced by the 2nd-4th challenges. IL-33 mRNA transcription was also induced after these challenges. An immunohistochemical analysis revealed that the cellular sources of IL-33 after the 1st challenge were mainly bronchial epithelial cells, while those after the 3rd challenge were not only the epithelial cells, but also inflammatory cells that infiltrated the lungs. Flow cytometric analyses indicated that approximately 20% and 10% of the IL-33-producing cells in the lungs were M2 macrophages and conventional dendritic cells, respectively. A systemic treatment with dexamethasone before the 1st challenge potently suppressed the IL-33 production. When dexamethasone was administered before the respective challenges, production of the IL-33 protein and the infiltration of IL-33-producing M2 macrophages and dendritic cells into the lungs in the 3rd challenge were also suppressed. In conclusion, the cellular sources of IL-33 in the lungs were dynamically altered during multiple challenges: not only bronchial epithelial cells, but also the M2 macrophages and dendritic cells that infiltrated the lungs produced IL-33. The production of IL-33 was susceptible to the glucocorticoid treatment.

Keywords: Asthma; Dendritic cells; Epithelial cells; Glucocorticoid; Interleukin-33; M2 macrophages.

MeSH terms

  • Animals
  • Antigens / immunology*
  • Dexamethasone / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Glucocorticoids / pharmacology*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33 / biosynthesis*
  • Interleukin-33 / genetics
  • Leukocytes / drug effects
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Lung / drug effects*
  • Lung / immunology
  • Lung / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Ovalbumin / immunology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology


  • Antigens
  • Glucocorticoids
  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • RNA, Messenger
  • Receptors, Interleukin
  • Dexamethasone
  • Ovalbumin