NF-κB Is a Negative Regulator of IL-1β Secretion as Revealed by Genetic and Pharmacological Inhibition of IKKβ

Greten, Florian R.; Arkan, Melek C.; Bollrath, Julia; Hsu, Li-Chung; Goode, Jason; Miething, Cornelius; Göktuna, Serkan Ismail; Neuenhahn, Michael; Fierer, Joshua; Paxian, Stephan; Rooijen, Nico van; Xu, Yajun; Ocain, Timothy D.; Jaffee, Bruce; Busch, Dirk H.; Duyster, Justus; Schmid, Roland M.; Eckmann, Lars; Karin, Michael

doi:10.1016/j.cell.2007.07.009

Cited by 573 publications

(591 citation statements)

References 56 publications

Supporting

Mentioning

542

Contrasting

Unclassified

Order By: Relevance

“…These observations, similar to those obtained with NLRP3 (7), reveal that it would be simplistic to deduce the physiologic role of NLRP12 only from in vitro assays, especially because it is well established that NF-B and IL-1␤ are part of interconnected networks (9,10), and that NF-B acts both on the induction and on the resolution of inflammation (10,11). Notably, the mechanisms underlying NLRP12-associated disorders may also vary according to the nature of the disease-causing mutation.…”

Section: Discussionsupporting

confidence: 68%

Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes

Jéru

Borgne

Cochet

et al. 2011

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation.Methods. NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-B activation.Results. A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotidebinding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-B activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12-associated disorders (NLRP12AD).Conclusion. Given the rarity of known NLRP12-associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.Periodic fever syndromes (PFS) are Mendelian autoinflammatory disorders characterized by recurrent episodes of fever and systemic inflammation, sometimes complicated by amyloidosis. Recently, the first two recognized disease-causing mutations (a nonsense mutation and a splice site mutation) have been identified in the NLRP12 gene (also known as NALP12 or MONARCH-1) in patients with a clinical picture suggestive of a cryopyrin-associated periodic syndrome (CAPS) (1). CAPS represent a subgroup of PFS comprising the familial cold-induced autoinflammatory syndrome, the Muckle-Wells syndrome, and the chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease. These three disorders have been associated with mutations in NLRP3, which, like NLRP12, is a member of the NLRP family.Diagnosis of PFS remains difficult, for the following reasons: there is no pathognomonic sign of these disorders; many patients present with symptoms that do not fit any classification; the majority of patients referred today are sporadic cases, precluding intrafamilial segregation analyses; and the majority of mutations identified in PFS genes correspond to missense variations, whose deleterious effects are often questionable.

show abstract

Section: Discussionsupporting

confidence: 68%

Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes

Jéru

Borgne

Cochet

et al. 2011

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…LPS is a known p65‐NF‐kB activator necessary for NLRP3 expression, but often a second stimulus such as ATP is required to activate inflammasomes (Greten et al ., 2007; Bauernfeind et al ., 2009). To evaluate p65‐NF‐kB activation, cell fractionation was performed.…”

Section: Resultsmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

View full text Add to dashboard Cite

SummaryGaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

show abstract

“…Accordingly, these mice exhibited decline in tumor load, most of tumors presented in these mice were smaller in size compared to tumors in WT mice (72), which indicates that the inflammation-related release of cytokines might target epithelium thus promoting the expansion of transformed cells in an NF-B dependent manner, the expression of most of cytokines and growth factors characterizing the inflammatory process and involved in tumor progression relies on NF-B activation in immune cells (84). Taken …”

Section: The Role Of Nf-b In Promoting Carcinogenesis Of Colorectalmentioning

confidence: 94%

“…Activation of NF-B in epithelial cells is directly involved in the promotion and progression steps of colitis associated colorectal cancer. To investigate the role of NF-B in CRC development, conditional knockout mice lacking of the expression of IKKβ in the epithelial cells in AOM/DSS colitis associated CRC model was used by Greten et al (72), who demonstrated that the number of colon tumors reduced (but not tumor size), although inflammation was not reduced comparing wild type with knockout mice. They also showed that the decrease in tumor incidence was accompanied by increased epithelial apoptosis.…”

Section: The Role Of Nf-b In Promoting Carcinogenesis Of Colorectalmentioning

confidence: 99%

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

et al. 2009

View full text Add to dashboard Cite

There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B (NF-B), a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-B activation in inflammatory bowel diseases (

show abstract

NF-κB Is a Negative Regulator of IL-1β Secretion as Revealed by Genetic and Pharmacological Inhibition of IKKβ

Cited by 573 publications

References 56 publications

Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes

Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

Contact Info

Product

Resources

About