BACKGROUND Particular neutralizing mAbs to certain cytokines act as agonists in vivo through protection of the cytokine's active site and prolongation of its half-life. Although this principle might be useful for targeted immunotherapy, its role in the pathogenesis of inflammation and autoimmunity is unclear. OBJECTIVE We sought to determine whether slight, structurally nonrelevant modifications of the prototypic proinflammatory cytokine IL-1β during an immune response could elicit polyclonal anti-IL-1β antibody responses that modulated IL-1β's in vivo activity. METHODS We engineered 2 different IL-1β variants, thereby mimicking the process of cytokine modification occurring during inflammation, and conjugated them to virus-like particles, followed by immunization of mice. The resulting polyclonal anti-IL-1β antibody responses were assessed by using in vitro and in vivo assays, as well as 2 relevant (auto-) inflammatory murine models. RESULTS Although antibody responses generated to one variant were potently inhibiting IL-1β, antibody responses induced by the other variant even potentiated the in vivo effects of IL-1β; the latter led to enhanced morbidity in 2 different IL-1β-mediated mouse models, including a model of inflammatory bowel disease and an inflammatory arthritis model. CONCLUSION These data demonstrate that endogenous polyclonal anti-cytokine antibody responses can enhance the cytokine's activity in inflammatory and autoimmune diseases.