Several studies have provided powerful proof of concept for the notion that single cytokine targeting can manifest effective immune suppression even in the context of complex networks of cytokine activities. We have studied the biology and functional expression of the innate response cytokine IL-15 and, more recently, members of the IL-1/IL-1 receptor superfamily in inflammatory synovitis. These cytokines are characterised by early upregulation during inflammatory responses and characteristic functional synergy and cross-regulation in the intact immune response. IL-15 is an IL-2-like cytokine of 15 kDa that possesses broad proinflammatory activities via its heterotrimeric receptor (IL-15Rα/IL-15/2Rβ/common γ), including promoting T-cell maturation, activation, and cytokine production, natural killer cell maturation and effector function, neutrophil activation, dendritic cell activation, endothelial cell rescue from apoptosis, macrophage activation and B-cell activation and isotype switching. IL-15 is expressed at mRNA and protein levels in several inflammatory arthritides including rheumatoid arthritis. When targeted in rodent models of inflammation using either soluble IL-15Rα or modified IL-15 mutant fusion proteins, amelioration of onset and of existing arthritis is observed. A recent phase I study in which a fully human IgG1 monoclonal antibody (HuMax-IL15; Genmab, Copenhagen, Denmark) was administered to 30 patients with active rheumatoid arthritis indicated that IL-15 blockade was well tolerated up to 8 weeks, with early indications of efficacy detected. We have now observed close interactions between IL-15 and IL-1 receptor superfamily signalling in promoting T-cell activation. Specifically, IL-15 synergises with the TLR2 ligand BLP to promote memory T-cell activation (co-stimulatory) and also via a cell membrane-dependent pathway to promote adjacent macrophage activation and tumour necrosis factor release. We have also observed that a further member of the IL-1 receptor superfamily, namely ST2, is expressed in synovial fibroblasts. Membrane-bound ST2 negatively regulates type I IL-1 receptor and TLR4 signalling by sequestrating the adaptors MyD88 and Mal. Intriguingly, soluble ST2 suppresses development of collagen-induced arthritis in DBA/1 mice if given prophylactically, and also established collagen-induced arthritis if administered after disease onset. Together these data suggest that complex interactions between the common γ-receptor chain and IL-1 receptor superfamily signalling cytokines are of importance in developing synovial inflammatory responses and that elucidation of these pathways offers therapeutic utility.