IL-36α exerts pro-inflammatory effects in the lungs of mice

PLoS One. 2012;7(9):e45784. doi: 10.1371/journal.pone.0045784. Epub 2012 Sep 20.


Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5- IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36α (IL-1F6) and test the hypothesis that IL-36α acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36α induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1αβ(-/-) mice in vivo. IL-36α induced neutrophil influx was also associated with increased mRNA expression of neutrophil-specific chemokines CXCL1 and CXCL2 in the lungs of C57BL/6 and IL-1αβ(-/-) mice in vivo. In addition, intratracheal instillation of IL-36α enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1αβ(-/-) mice in vivo. Furthermore, in vitro incubation of CD11c(+) cells with IL-36α resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNFα. IL-36α increased the expression of the co-stimulatory molecule CD40 and enhanced the ability of CD11c(+) cells to induce CD4(+) T cell proliferation in vitro. Furthermore, stimulation with IL-36α activated NF-κB in a mouse macrophage cell line. These results demonstrate that IL-36α acts as a pro-inflammatory cytokine in the lung without the contribution of IL-1α and IL-1β. The current study describes the pro-inflammatory effects of IL-36α in the lung, demonstrates the functional redundancy of IL-36α with other agonist cytokines in the IL-1 and IL-36 cytokine cluster, and suggests that therapeutic targeting of IL-36 cytokines could be beneficial in inflammatory lung diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD11 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytokines / physiology
  • Gene Expression Regulation
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology*
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-1 / physiology*
  • Interleukin-1alpha / deficiency
  • Interleukin-1alpha / genetics
  • Interleukin-1beta / deficiency
  • Interleukin-1beta / genetics
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Neutrophil Infiltration
  • Pneumonia / immunology
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • Spleen / immunology
  • Spleen / pathology


  • CD11 Antigens
  • Cytokines
  • Inflammation Mediators
  • Interleukin-1
  • Interleukin-1alpha
  • Interleukin-1beta
  • NF-kappa B
  • interleukin 1F6, mouse