Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1β and IL-18 release

Aluminum hydroxide (Alum) is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. In this study, we show that Alum activates caspase-1 and induce secretion of mature IL-1 beta and IL-18. Human PBMC or dendritic cells stimulated with pure TLR4 and TLR2 agonists released only traces of IL-1 beta or IL-18, despite the fact that the IL-1 beta mRNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus Alum released large amount of IL-1 beta and IL-18. Alum-induced IL-1 beta and IL-18 production was not due to enhancement of TLR signaling but rather reflected caspase-1 activation and in mouse dendritic cells occurred in a MyD88-independent fashion. Secretion of other proinflammatory cytokines such as IL-8 was not affected by Alum treatments. However, TLR-induced production of IL-10 was increased and that of IFN-gamma-inducible protein decreased by Alum cotreatment. Considering the inummostimulatory activities of these cytokines and the ability of IL-1 beta to act as adjuvant, our results suggest a mechanism for the adjuvanticity of Alum.