IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-γ and natural killer cells

Shigeki Matsubara, Katsuyuki Takeda, Taku Kodama, Anthony Joetham, Nobyaki Miyahara, Toshiyuki Koya, Christina H. Swasey, Masakazu Okamoto, Azzeddine Dakhama, Erwin W. Gelfand

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Abstract

IL-18 is known to induce IFN-γ production, which is enhanced when combined with IL-2. In the present study, we investigated whether the combination of exogenous IL-2 and IL-18 alters airway hyperresponsiveness (AHR) and airway inflammation. Sensitized mice exposed to ovalbumin (OVA) challenge developed AHR, inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and increases in levels of Th2 cytokines and goblet cell numbers. The combination of IL-2 and IL-18, but neither alone, prevented these changes while increasing levels of IL-12 and IFN-γ. The combination of IL-2 and IL-18 was ineffective in IFN-γ-deficient and signal transducer and activator of transcription (STAT)4-deficient mice. Flow cytometry analysis showed significant increases in numbers of IFN-γ-positive natural killer (NK) cells in the lung after treatment with the combination therapy, and transfer of lung NK cells isolated from sensitized and challenged mice treated with the combination significantly suppressed AHR and BAL eosinophilia. These data demonstrate that the combination of IL-2 and IL-18 prevents AHR and airway inflammation, likely through IL-12-mediated induction of IFN-γ production in NK cells.

Original languageEnglish
Pages (from-to)324-332
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume36
Issue number3
DOIs
Publication statusPublished - Mar 1 2007

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Keywords

  • Airway hyperresponsiveness
  • IFN-γ
  • IL-18
  • IL-2
  • STAT4

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Matsubara, S., Takeda, K., Kodama, T., Joetham, A., Miyahara, N., Koya, T., Swasey, C. H., Okamoto, M., Dakhama, A., & Gelfand, E. W. (2007). IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-γ and natural killer cells. American journal of respiratory cell and molecular biology, 36(3), 324-332. https://doi.org/10.1165/rcmb.2006-0231OC