**8.1. IL-19**

Sakurai et al. [174] showed that IL-19 was produced by cells of human RA synovial tissue. The majority of IL-19 positive cells were vimentin- and CD68-positive, indicating that fibro‐ blasts and macrophages were the main sources of IL-19 in RA synovium. From a functional perspective, synovial tissue lining and sublining layers were both identified with anti-IL-20R1 and anti-IL-20R2 antibodies.

IL-19 activated synoviocyte STAT3 and, downstream, STAT3 activation caused up-regula‐ tion of IL-6 and IL-19 gene expression whilst decreasing synoviocyte apoptosis induced by serum-starvation [174], a change which may predict the role of IL-19 in the development of synovial hyperplasia [30, 96]. However, the role of IL-19 in RA relative to its activation of signal transduction was further complicated by the findings of Alanärä et al. [175] who showed that IL-1β, an activator of the MAPK pathway [176], also increased the level of IL-19 in peripheral blood mononuclear cells *in vitro*. Combined with other data this result showed that in RA joints IL-19 expression was the highest of all of the IL-10 family cytokines. Fur‐ thermore, these results suggested that IL-19 played a significant role in synovial tissue in‐ flammation, with the caveat that further consideration of IL-19 as a target for intervention in in RA must focus on the relative level of JAK/STAT activation of JAK/STAT versus activa‐ tion of the other signaling pathways.

IL-19 was highly expressed in synovial tissue and, in particular, expressed in fibroblasts iso‐ lated from rats with collagen-induced arthritis (CIA) [177]. Of note, treating these rats with a anti-IL-19 antibody, 1BB1, reduced arthritis severity which was accompanied by the lower level of boney erosions and an improvement in the quality of subchondral bone. Moreover, treatment of rats with CIA with 1BB1 reduced the expression of TNF-α, IL-1β, IL-6 and Re‐ ceptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) genes in synovial tissue and also lowered IL-6 levels in serum. Synovial fibroblasts isolated from rats with CIA respond‐ ed to treatment with IL-19 in a similar fashion seen with synovial tissue *in situ* where in‐ creased synthesis of TNF-α, IL-1β, IL-6 and RANKL was detected.

There is now compelling evidence that IL-19-mediated activation of STAT3 was associated with the development and progression of inflammatory arthritis which was characterized by the elevated expression of many of the pro-inflammatory cytokines pertinent to human RA joint destruction. These data also showed that the rat CIA model could be further ex‐ ploited to determine the extent to which specific dampening or up-regulation of STAT-re‐ sponsive cytokine genes would ameliorate inflammatory responses associated with CIA.
