Autocrine Induction of the Human Pro-IL-1β Gene Promoter by IL-1β in Monocytes

Toda, Yoshitomo; Tsukada, Junichi; Misago, M; Kominato, Yoshihiko; Auron, Philip E.; Tanaka, Yoshiya

doi:10.4049/jimmunol.168.4.1984

Cited by 63 publications

(45 citation statements)

References 55 publications

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“…In mouse cells, but not in human cells, there is a clear requirement in vitro for two signals to activate the inflammasome and to produce pro-IL-1β (LPS and alum), yet it is not clear what is providing the first signal for alum in vivo (or other Nalp3 stimuli including MSU). We have preliminary evidence from in vitro studies that IL-1β itself can prime macrophages for alum-induced inflammasome activation (data not shown); these results are consistent with previous reports that IL-1β can act in an autocrine manner to induce its own gene expression 23 . Other groups have similarly seen macrophage priming with cytokines (for example TNF-α) instead of LPS 13 .…”

supporting

confidence: 92%

Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants

Eisenbarth

Colegio²,

O’Connor³

et al. 2008

Nature

1,365

1,178

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Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system 1,2 . Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1β and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.Reprints and permissions information is available at www.nature.com/reprints.Correspondence and requests for materials should be addressed to R.A.F. (richard.flavell@yale.edu). Supplementary Information is linked to the online version of the paper at www.nature.com/nature. [12][13][14][15] . We formed the hypothesis that the particulate nature of alum might be recognized by NLRs, much like crystalline MSU. To test whether alum activates the Nalp3 inflammasome, we used primary peritoneal macrophages from mice deficient in critical signalling components of the Nalp3 inflammasome. Because inflammasome activation requires two signals for the production of mature IL-1β, we first primed macrophages with lipopolysaccharide (LPS) and then exposed them to aluminium adjuvants. Consistent with previous reports [13][14][15] , aluminium adjuvants induced the production of IL-1β and IL-18 from wild-type (C57BL/6; WT) primary murine macrophages ( Fig. 1a, d), bone-marrow-derived macrophages ( Supplementary Fig. 1a) and bone-marrowderived dendritic cells ( Supplementary Fig. 1b) in vitro. IL-1β secretion was dependent on the dose of alum (Fig. 1b) and peaked between 8 and 10 h of stimulation with alum in WT macrophages, but continued out to 48 h ( Fig. 2c and data not shown). HHS Public AccessIn contrast, macrophages from animals deficient in Nalp3, ASC or caspase-1 failed to produce IL-1β or IL-18 on stimulation with multiple types of aluminium adjuvant (Fig. 1c, d, Supplementary Fig. 1b and data not shown). Another member ...

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supporting

confidence: 92%

Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants

Eisenbarth

Colegio²,

O’Connor³

et al. 2008

Nature

1,365

1,178

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“…A modulatory activity of PU.1 has been recently reported for the cytokines IL-1b and IL-12 p40. 25 Our results show that the À1082A allele confers optimal binding affinity for the transcription factor PU.1 which inhibits gene expression. Therefore, we …”

Section: Discussionmentioning

confidence: 65%

Differential regulation of interleukin-10 production by genetic and environmental factors – a twin study

et al. 2002

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Interleukin-10 (IL-10) has a critical role in the regulation of immune responses. The relative contribution of genetic and environmental factors to IL-10 production is under debate. We performed a twin study in 246 monozygotic and dizygotic twins to assess the heritability of IL-10 production after LPS stimulation in whole blood. In addition, the influence of promoter single nucleotide polymorphisms (À1082, À819 and À592) on transcriptional activity and their binding to nuclear factors was studied in luciferase reporter gene and electrophoretic mobility shift assays. IL-10 production showed a genetic determination with a heritability of 0.5. Decreasing body mass index (BMI), smoking and female gender lead to decreased IL-10 production. In monocytes, the À1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of À1082A promoter haplotypes. Genetic determination of IL-10 secretion is probably lower than that previously reported. Fifty percent of the observed variability explained by genetic factors. Female individuals produce less IL-10 than male subjects. Environmental factors like smoking and decreasing BMI exert suppressing effects on IL-10 production. Although the À1082A allele shows higher binding affinity to the PU.1 transcription factor and lower transcriptional activity, this polymorphism probably explains only a small fraction of the observed heritability.

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“…The present results confirm this notion, but they also show that microglia may not be the responder cells to IL-1. This is different from some peripheral monocytes in which IL-1 induces its own expression 32. Therefore, unless microglia is activated to the state of an IL-1R1-expressing cell, it is not likely to trigger self-amplifying neuroinflammation in the brain.…”

Section: Discussionmentioning

confidence: 82%

Interleukin-1 exerts distinct actions on different cell types of the brain in vitro

An¹,

Chen²,

Quan³

2011

JIR

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Interleukin-1 (IL-1) is a critical neuroinflammatory mediator in the central nervous system (CNS). In this study, we investigated the effect of IL-1 on inducing inflammation-related gene expression in three astrocyte, two microglial, and one brain endothelial cell line. Interleukin-1 beta (IL-1β) is found to be produced by the two microglial cell lines constitutively, but these cells do not respond to IL-1β stimulation. The three astrocyte cell lines responded to IL-1β stimulation by expressing MCP-1, CXCL-1, and VCAM-1, but different subtypes of astrocytes exhibited different expression profiles after IL-1β stimulation. The brain endothelial cells showed strongest response to IL-1β by producing MCP-1, CXCL-1, VCAM-1, ICAM-1, IL-6, and COX-2 mRNA. The induction of endothelial COX-2 mRNA is shown to be mediated by p38 MAPK pathway, whereas the induction of other genes is mediated by the NF-κB pathway. These results demonstrate that IL-1 exerts distinct cell type-specific action in CNS cells and suggest that IL-1-mediated neuroinflammation is the result of the summation of multiple responses from different cell types in the CNS to IL-1.

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Autocrine Induction of the Human Pro-IL-1β Gene Promoter by IL-1β in Monocytes

Cited by 63 publications

References 55 publications

Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants

Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants

Differential regulation of interleukin-10 production by genetic and environmental factors – a twin study

Interleukin-1 exerts distinct actions on different cell types of the brain in vitro

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