Hypo-osmotic Stress Drives IL-33 Production in Human Keratinocytes-An Epidermal Homeostatic Response

J Invest Dermatol. 2019 Jan;139(1):81-90. doi: 10.1016/j.jid.2018.07.023. Epub 2018 Aug 16.


Although inflammation has traditionally been considered a response to either exogenous pathogen-associated signals or endogenous signals of cell damage, other perturbations of homeostasis, generally referred to as stress, may also induce inflammation. The relationship between stress and inflammation is, however, not well defined. Here, we describe a mechanism of IL-33 induction driven by hypo-osmotic stress in human keratinocytes and also report interesting differences when comparing the responsiveness of other inflammatory mediators. The induction of IL-33 was completely dependent on EGFR and calcium signaling, and inhibition of calcium signaling not only abolished IL-33 induction but also dramatically changed the transcriptional pattern of other cytokines upon hypo-osmotic stress. IL-33 was not secreted but instead showed nuclear sequestration, conceivably acting as a failsafe mechanism whereby it is induced by potential danger but released only upon more extreme homeostatic perturbations that result in cell death. Finally, stress-induced IL-33 was also confirmed in an ex vivo human skin model, translating this mechanism to a potential tissue-relevant signal in the human epidermis. In conclusion, we describe hypo-osmotic stress as an inducer of IL-33 expression, linking cellular stress to nuclear accumulation of a strong proinflammatory cytokine.

MeSH terms

  • Cells, Cultured
  • Cytokines / metabolism
  • Gene Expression Regulation*
  • Homeostasis
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-33 / biosynthesis
  • Interleukin-33 / genetics*
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Microscopy, Phase-Contrast
  • Osmotic Pressure
  • RNA / genetics
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction


  • Cytokines
  • Interleukin-33
  • RNA