Cyclic stretch induced IL-33 production through HMGB1/TLR-4 signaling pathway in murine respiratory epithelial cells

PLoS One. 2017 Sep 12;12(9):e0184770. doi: 10.1371/journal.pone.0184770. eCollection 2017.


Interleukin 33 (IL-33), an inflammatory and mechanically responsive cytokine, is an important component of a TLR4-dependent innate immune process in mucosal epithelium. Although TLR4 also plays a role in sensing biomechanical stretch, a pathway of stretch-induced TLR4-dependent IL-33 biosynthesis has not been revealed. In the current study, we show that short term (6 h) cyclic stretch (CS) of cultured murine respiratory epithelial cells (MLE-12) increased intracellular IL-33 expression in a TLR4 dependent fashion. There was no detectable IL-33 in conditioned media in this interval. CS, however, increased release of the notable alarmin, HMGB1, and a neutralizing antibody (2G7) to HMGB1 completely abolished the CS mediated increase in IL-33. rHMGB1 increased IL-33 synthesis and this was partially abrogated by silencing TLR4 suggesting additional receptors for HMGB1 are involved in its regulation of IL-33. Collectively, these data reveal a HMGB1/TLR4/IL-33 pathway in the response of respiratory epithelium to mechanical stretch.

MeSH terms

  • Animals
  • Cell Line
  • HMGB1 Protein / metabolism*
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Mechanotransduction, Cellular*
  • Mice
  • Respiratory Mucosa / metabolism*
  • Second Messenger Systems
  • Stress, Mechanical
  • Toll-Like Receptor 4 / metabolism*


  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-33
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4