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

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

Author information

1
Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
2
Department of Microbiology, Federal University of Minas, Gerais, Brazil.
3
Department of General Biology, Federal University of Minas, Gerais, Brazil.
4
Xencor, Monrovia, USA.
5
Molecular Immunology and Embryology, Centre National de la Recherche Scientifique, Orléans, France.

Abstract

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

PMID:
26449770
DOI:
10.1002/eji.201545798
[Indexed for MEDLINE]
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