Regulation of IL (Interleukin)-33 Production in Endothelial Cells via Kinase Activation and Fas/CD95 Upregulation

Arterioscler Thromb Vasc Biol. 2020 Nov;40(11):2619-2631. doi: 10.1161/ATVBAHA.120.314832. Epub 2020 Sep 10.


Objective: The occurrence of new blood vessel formation in the lungs of asthmatic patients suggests a critical role for airway endothelial cells (ECs) in the disease. IL-33 (Interleukin-33)-a cytokine abundantly expressed in human lung ECs-recently emerged as a key factor in the development of allergic diseases, including asthma. In the present study, we evaluated whether mouse and human ECs exposed to the common Dermatophagoides farinae allergen produce IL-33 and characterized the activated signaling pathways. Approach and Results: Mouse primary lung ECs were exposed in vitro to D farinae extract or rmIL-33 (recombinant murine IL-33). Both D farinae and rmIL-33 induced Il-33 transcription without increasing the IL-33 production and upregulated the expression of its receptor, as well as genes involved in angiogenesis and the regulation of immune responses. In particular, D farinae and rmIL-33 upregulated Fas/Cd95 transcript level, yet without promoting apoptosis. Inhibition of caspases involved in the Fas signaling pathway, increased IL-33 protein level in ECs, suggesting that Fas may decrease IL-33 level through caspase-8-dependent mechanisms. Our data also showed that the NF-κB (nuclear factor-κB), PI3K/Akt, and Wnt/β-catenin pathways regulate Il-33 transcription in both mouse and human primary ECs.

Conclusions: Herein, we described a new mechanism involved in the control of IL-33 production in lung ECs exposed to allergens.

Keywords: blood vessels; endothelial cells; endothelium; inflammation; lung.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Dermatophagoides / pharmacology*
  • Caspase 8 / metabolism
  • Cell Line
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / immunology
  • Enzyme Activation
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / enzymology
  • Human Umbilical Vein Endothelial Cells / immunology
  • Humans
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism
  • Interleukin-33 / pharmacology*
  • Lung / blood supply*
  • Mice
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Up-Regulation
  • Wnt Signaling Pathway
  • fas Receptor / genetics
  • fas Receptor / metabolism*


  • Antigens, Dermatophagoides
  • FAS protein, human
  • Fas protein, mouse
  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-33
  • fas Receptor
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Casp8 protein, mouse
  • Caspase 8