Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta 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-1beta and IL-18. Human PBMC or dendritic cells stimulated with pure TLR4 and TLR2 agonists released only traces of IL-1beta or IL-18, despite the fact that the IL-1beta mRNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus Alum released large amount of IL-1beta and IL-18. Alum-induced IL-1beta 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 immunostimulatory activities of these cytokines and the ability of IL-1beta to act as adjuvant, our results suggest a mechanism for the adjuvanticity of Alum.
Li
Hanfen
H
Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Nookala
Suba
S
Re
Fabio
F
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000536:Aluminum Hydroxide / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000502:physiology
D000276:Adjuvants, Immunologic; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D020382:Interleukin-18; D053583:Interleukin-1beta; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D016753:Interleukin-10; D000536:Aluminum Hydroxide; D020170:Caspase 1