NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.
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.
Greten
Florian R
FR
Second Department of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Germany. florian.greten@lrz.tum.de
Arkan
Melek C
MC
Bollrath
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Li-Chung
LC
Goode
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Miething
Cornelius
C
Göktuna
Serkan I
SI
Neuenhahn
Michael
M
Fierer
Joshua
J
Paxian
Stephan
S
Van Rooijen
Nico
N
Xu
Yajun
Y
O'Cain
Timothy
T
Jaffee
Bruce B
BB
Busch
Dirk H
DH
Duyster
Justus
J
Schmid
Roland M
RM
Eckmann
Lars
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Karin
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D000818:Animals; D017209:Apoptosis; D002243:Carbolines / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000097:blood