To gain insight into the mechanisms of the antiinflammatory effect of tumor necrosis factor α (TNFα)–induced protein 6 (Tnfip6) in arthritis, using Tnfip6‐deficient animals.

TNFα‐stimulated gene 6 (TSG‐6) coding for Tnfip6 was disrupted. Tnfip6‐deficient mice were backcrossed into proteoglycan‐induced arthritis (PGIA)–susceptible BALB/c mice, and arthritis was induced by systemic immunization with cartilage proteoglycan (PG). Thioglycollate‐induced sterile peritonitis was also assessed, to monitor the early events of neutrophil extravasation in wild‐type and Tnfip6‐deficient mice in the presence or absence of treatment with recombinant murine Tnfip6.

The onset of PGIA was similar, but progression and severity were significantly greater, in Tnfip6‐deficient mice compared with wild‐type BALB/c mice. However, this was not associated with enhanced T or B cell responses to cartilage PGs, but rather, an early and more extensive infiltration of the synovium with neutrophil leukocytes was the most prominent histopathologic feature of PGIA in Tnfip6‐deficient mice. This was accompanied by elevated serum levels of interleukin‐6 and amyloid A, and significantly increased activities of the enzymes plasmin, myeloperoxidase, and neutrophil elastase in the inflamed paw joints of Tnfip6‐null mice, when compared with that of the wild‐type littermates. Loss of control over several components of inflammation resulted in extensive and rapid cartilage degradation, bone erosion, joint ankylosis, and deformities in Tnfip6‐null animals. In support of the antiinflammatory effect of Tnfip6 via the inhibition of polymorphonuclear (PMN) cell efflux, neutrophil invasion during thioglycollate‐induced peritonitis was 2‐fold higher in Tnfip6‐deficient animals than in wild‐type animals, but was dramatically suppressed by intravenous injection of recombinant murine Tnfip6.

Tnfip6 is a multifunctional antiinflammatory protein that is produced at the site of inflammation and can be retained by the hyaluronan‐rich extracellular matrix. A major effect of Tnfip6 is the inhibition of the extravasation of PMN cells, predominantly neutrophils, into the site of inflammation, most likely via a CD44/hyaluronan/Tnfip6‐mediated blocking mechanism.