TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage

Mucosal Immunol. 2011 Jan;4(1):102-11. doi: 10.1038/mi.2010.57. Epub 2010 Sep 15.


Toll-like receptor-5 (TLR5)-mediated detection of flagellin induces nuclear factor (NF)-κB-mediated transcription of host defense gene expression, whereas recognition of intracellular flagellin by interleukin (IL)-1-converting enzyme protease-activation factor (IPAF) results in maturation/secretion of the inflammasome cytokine IL-1β. The potent effects of IL-1β are counter-regulated by secretory IL-1 receptor antagonist (sIL-1Ra). We studied the roles of flagellin receptors in regulating the expression of IL-1β and sIL-1Ra and their subsequent roles in inflammation. Flagellin induced sIL-1Ra in intestinal epithelia and macrophages in a dose- and time-dependent manner, whereas IL-1β was only induced in macrophages. In vivo, flagellin-induced sIL-1Ra, but not IL-1β, was absolutely dependent upon TLR5 expressed on non-hemopioetic cells. Thus, loss of TLR5 increased the IL-1β/sIL-1Ra ratio on flagellin treatment, which correlated with increased inflammatory pathology in response to this product. Furthermore, the flagellin/TLR5 interaction was important for the induction of sIL-1Ra and limiting inflammatory pathology on Salmonella infection. Finally, reduced sIL-1Ra levels in TLR5KO mice correlated with spontaneous colitis. Taken together, we demonstrate that intestinal epithelia, despite not expressing IL-1β, secrete sIL-1Ra in a TLR5-dependent manner suggesting that loss of TLR5 may promote inflammation by increasing IL-1β activity. Thus, optimizing the balance between inflammasome cytokines and their endogenous inhibitors might prove a useful strategy to treat inflammatory disorders.

Publication types

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

MeSH terms

  • Animals
  • Caspase 1 / metabolism
  • Cell Line
  • Colitis / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flagellin / immunology*
  • Gene Expression
  • Gene Expression Regulation
  • Inflammasomes
  • Inflammation / immunology*
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Interleukin-1beta / genetics*
  • Interleukin-1beta / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Salmonella Infections / immunology
  • Toll-Like Receptor 5 / immunology*
  • Toll-Like Receptor 5 / metabolism


  • Inflammasomes
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • NF-kappa B
  • RNA, Messenger
  • Toll-Like Receptor 5
  • Flagellin
  • Caspase 1