Increased their production of IL-1b upon FccRIII ligation, and that this effect could be mimicked by co-culture with primary fibroblasts derived from mouse synovium. Further, we found that this relationship was reciprocal, in that MCs activated via ST2 augmented IL-33 expression in co-cultured FLS, representing a potential amplification loop. The in vivo importance of these in vitro observations was suggested by the reduced intensity of K/BxN arthritis in ST22/2 mice, a phenotype associated by others with altered MC activation. Beyond IL-1b, we found that IL-33 priming of MCs enhanced FccRIII-mediated release of multiple other mediators, including CXCL2. The CXCL2 receptor CXCR2 is required for the development of full pathology in K/BxN arthritis, and in particular for neutrophil recruitment. Our findings therefore develop further our understanding of mechanisms by which MCs help recruit neutrophils to the inflamed joint. These results are consistent with published data showing that IL-33 amplifies mediator production resulting from stimulation of MCs via IgE, since both FccRIII and FceRI signal via a common Fc receptor c chain. Further, our results confirm that IL33 can itself drive MC production of a range of mediators, including the unusual combination of IL-6 and IL-2 that could potentially contribute to the subversion of regulatory T cell function. Such direct stimulation of MCs may contribute to inflammatory arthritis, particularly in chronic synovitis, when the population of Ponatinib 943319-70-8 synovial MCs is often markedly expanded. However, our results suggest an alternate mechanism by which IL-33 contributes to acute MC activation in IgG-mediated arthritis. In K/BxN arthritis, the MC-dependent “flare” begins within minutes of serum administration, a timeframe probably too short for de novo IL-33 synthesis. Rather our data suggest that constitutive signals mediated via IL-33 promote immune complex responsiveness of synovial MCs, defining therefore a new model for a permissive role of IL-33 in MC-dependent immune complex disease. Whereas IL-33 pre-incubation induces accumulation of mRNA for key proinflammatory cytokines whose production by subsequent FccRIII ligation is markedly enhanced, we hypothesize that such “preloading” of MC by IL-33 represents an important component of the priming mechanism, though other factors may also be involved. Our results also expand appreciation of the integral relationship between MCs and fibroblasts. We previously demonstrated a profound effect of fibroblasts on the development of MCs. The current work builds upon these studies, showing that IL-33 is a key mediator by which fibroblasts prime MCs for activation by IgG immune complexes. Given the known anatomic and functional associations of synovial MC with fibroblasts, these cells represent the most likely source of IL-33 in the joint, a possibility modeled by our in vitro co-culture system. However, endothelial cells or other IL-33-producing lineages, including MCs themselves, could potentially fulfill the same role. While our in vitro findings correspond well to the expected activity of MCs in arthritis, it is possible that our system fails to model all aspects of the in vivo biology. In particular, we observed evidence for reduced MC activation in ST22/2 animals exposed to K/BxN IgG, manifested as reduced flare magnitude. This result supports the observation that MC degranulation is impaired in ST22/2 mice administered K/BxN serum.