PT  - JOURNAL ARTICLE
AU  - G W Jones
AU  - C J Greenhill
AU  - J O Williams
AU  - M A Nowell
AU  - A S Williams
AU  - B J Jenkins
AU  - S A Jones
TI  - Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A
AID  - 10.1136/annrheumdis-2013-203771
DP  - 2013 Oct 01
TA  - Annals of the Rheumatic Diseases
PG  - 1738--1742
VI  - 72
IP  - 10
4099  - http://ard.bmj.com/content/72/10/1738.short
4100  - http://ard.bmj.com/content/72/10/1738.full
SO  - Ann Rheum Dis2013 Oct 01; 72
AB  - Objective Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology. Methods Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1−/− and gp130F/F:Il17a−/− mice. Joint pathology and associated peripheral TH-17 responses were compared. Results Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F:Stat1−/−) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a−/− mice. Here, loss of IL-17A had no impact on arthritis severity. Conclusions Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent.