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PMID: 17803913 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.

Cell ·Vol. 130 ·No. 5 ·2007-09-07 ·Pages 918-31

Greten FR, Arkan MC, Bollrath J, Hsu LC, Goode J, Miething C, Göktuna SI, Neuenhahn M, Fierer J, Paxian S, Van Rooijen N, Xu Y, O'Cain T, Jaffee BB, Busch DH, Duyster J, Schmid RM, Eckmann L, Karin M

Abstract

IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.

MeSH Terms
Animals Apoptosis Carbolines/pharmacology Caspase 1/metabolism Cell Line Disease Models, Animal Humans I-kappa B Kinase/antagonists & inhibitors,genetics,metabolism Interleukin-1beta/blood,genetics,metabolism Interleukin-6/blood Lipopolysaccharides Macrophages/drug effects,enzymology,immunology,metabolism,pathology Mice Mice, Knockout NF-kappa B/metabolism Neutrophil Infiltration Neutrophils/drug effects,enzymology,immunology,metabolism,pathology Niacinamide/analogs & derivatives,pharmacology Protein Kinase Inhibitors/pharmacology RNA, Messenger/metabolism Receptors, Interleukin-1/metabolism Serine Endopeptidases/metabolism Serpins/metabolism Shock, Septic/chemically induced,enzymology,immunology,metabolism,pathology Time Factors Transfection Tumor Necrosis Factor-alpha/blood
Chemicals
Carbolines Interleukin-1beta Interleukin-6 Lipopolysaccharides N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide NF-kappa B Protein Kinase Inhibitors RNA, Messenger Receptors, Interleukin-1 Serpins Tumor Necrosis Factor-alpha lipopolysaccharide, Escherichia coli O111 B4 Niacinamide I-kappa B Kinase Serine Endopeptidases Caspase 1
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Greten Florian R
Second Department of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Germany. florian.greten@lrz.tum.de
Arkan Melek C
Bollrath Julia
Hsu Li-Chung
Goode Jason
Miething Cornelius
Göktuna Serkan I
Neuenhahn Michael
Fierer Joshua
Paxian Stephan
Van Rooijen Nico
Xu Yajun
O'Cain Timothy
Jaffee Bruce B
Busch Dirk H
Duyster Justus
Schmid Roland M
Eckmann Lars
Karin Michael
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/j.cell.2007.07.009
Email
florian.greten@lrz.tum.de
Published
2007-09-07
Pages
918-31
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2134986
Subset
IM
Grants
NIDDK NIH HHS · P01 DK035108-190002 · United States
NIAID NIH HHS · AI061712 · United States
PHS HHS · E06486 · United States
NIAID NIH HHS · R01 AI043477-10 · United States
NIDDK NIH HHS · DK70867 · United States
NIDDK NIH HHS · P01 DK035108 · United States
NIDDK NIH HHS · DK35108 · United States
NIDDK NIH HHS · R01 DK070867 · United States
NIAID NIH HHS · R01 AI061712-04 · United States
NIAID NIH HHS · R01 AI056075-05 · United States
NIAID NIH HHS · R01 AI056075 · United States
NIDDK NIH HHS · P01 DK035108-190014 · United States
NIAID NIH HHS · R01 AI061712 · United States
NIAID NIH HHS · AI43477 · United States
NIAID NIH HHS · R01 AI043477 · United States
NIEHS NIH HHS · R01 ES006376 · United States
NIAID NIH HHS · AI56075 · United States
NIDDK NIH HHS · R01 DK070867-02 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2007.07.009 PMC Full Text View journal details
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