Interleukin-33 potentiates bleomycin-induced lung injury

Am J Respir Cell Mol Biol. 2013 Dec;49(6):999-1008. doi: 10.1165/rcmb.2013-0093OC.


The mechanisms of interstitial lung disease (ILD) remain incompletely understood, although recent observations have suggested an important contribution by IL-33. Substantial elevations in IL-33 expression were found in the lungs of patients with idiopathic pulmonary fibrosis and scleroderma lung disease, as well as in the bleomycin injury mouse model. Most of the observed IL-33 expression was intracellular and intranuclear, suggesting involvement of the full-length (fl) protein, but not of the proteolytically processed mature IL-33 cytokine. The effects of flIL-33 on mouse lungs were assessed independently and in combination with bleomycin injury, using recombinant adenovirus-mediated gene delivery. Bleomycin-induced changes were not affected by gene deficiency of the IL-33 receptor T1/ST2. Combined flIL-33 expression and bleomycin injury exerted a synergistic effect on pulmonary lymphocyte and collagen accumulation, which could be explained by synergistic regulation of the cytokines transforming growth factor-β, IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein\x{2013}1α, and tumor necrosis factor-α. By contrast, no increase in the levels of the Th2 cytokines IL-4, IL-5, or IL-13 was evident. Moreover, flIL-33 was found to increase the expression of several heat shock proteins (HSPs) significantly, and in particular HSP70, which is known to be associated with ILD. Thus, flIL-33 is a synergistic proinflammatory and profibrotic regulator that acts by stimulating the expression of several non-Th2 cytokines, and activates the expression of HSP70.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bleomycin / toxicity*
  • Cytokines / immunology
  • Disease Models, Animal
  • Female
  • Gene Expression
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / genetics
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Lung Diseases, Interstitial / etiology
  • Lung Diseases, Interstitial / immunology
  • Lung Diseases, Interstitial / pathology
  • Lung Injury / etiology*
  • Lung Injury / immunology
  • Lung Injury / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Processing, Post-Translational
  • Receptors, Interleukin / deficiency
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology


  • Cytokines
  • HSP70 Heat-Shock Proteins
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Inflammation Mediators
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Receptors, Interleukin
  • Bleomycin