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Aluminum Hydroxide Adjuvants Activate Caspase-1 and Induce IL-1 and IL-18 Release¹

Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163

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 and IL-18. Human PBMC or dendritic cells stimulated with pure TLR4 and TLR2 agonists released only traces of IL-1 or IL-18, despite the fact that the IL-1 mRNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus Alum released large amount of IL-1 and IL-18. Alum-induced IL-1 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--inducible protein decreased by Alum cotreatment. Considering the immunostimulatory activities of these cytokines and the ability of IL-1 to act as adjuvant, our results suggest a mechanism for the adjuvanticity of Alum.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a research grant from the Rheumatic Disease Research Core Center, University of Tennessee Health Science Center and by National Institutes of Health Grant AI-05466501 (to F.R.).

² Address correspondence and reprint requests to Dr. Fabio Re, Department of Molecular Sciences, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163. E-mail address: fre{at}utmem.edu

³ Abbreviations used in this paper: PRR, pattern recognition receptor; MSU, monosodium urate; Alum, aluminum hydroxide; MDP, muramyl dipeptide; DC, dendritic cell; IP-10, IFN--inducible protein.

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