Transmembrane TNF-α is sufficient for articular inflammation and hypernociception in a mouse model of gout

Eur J Immunol. 2016 Jan;46(1):204-11. doi: 10.1002/eji.201545798. Epub 2015 Nov 4.


Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1β are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1β, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1β protein and pro-IL-1β mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1β mRNA and IL-1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.

Keywords: Cytokines; Gout; Inflammation; Innate immune; Neutrophils; TNFIntroduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gout / complications
  • Gout / immunology*
  • Gout / metabolism
  • Hyperalgesia / etiology*
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Knee Joint
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Physical Stimulation
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism*
  • Uric Acid / adverse effects
  • Uric Acid / immunology


  • Interleukin-1beta
  • Membrane Proteins
  • Tumor Necrosis Factor-alpha
  • Uric Acid