IkappaBbeta is an essential co-activator for LPS-induced IL-1beta transcription in vivo.
Inhibitor of κB (IκB) β (IκBβ) represents one of the major primary regulators of NF-κB in mammals. In contrast to the defined regulatory interplay between NF-κB and IκBα, much less is known about the biological function of IκBβ. To elucidate the physiological role of IκBβ in NF-κB signaling in vivo, we generated IκBβ-deficient mice. These animals proved to be highly refractory to LPS-induced lethality, accompanied by a strong reduction in sepsis-associated cytokine production. In response to LPS, IκBβ is recruited to the IL-1β promoter forming a complex with the NF-κB subunits RelA/c-Rel required for IL-1β transcription. Further transcriptome analysis of LPS-stimulated wild-type and IκBβ-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-κB target genes is under control of IκBβ. Collectively, these findings provide an essential proinflammatory role for IκBβ in vivo, and establish a critical function for IκBβ as a transcriptional coactivator under inflammatory conditions.
II. Medizinische Klinik, Technische Universität München, 81675 München, Germany.
Melanie
M
Scheibel
Bettina
B
Klein
Heidrun
H
Merkle
Manon
M
Schulz
Ralph
R
Fritsch
Florian R
FR
Greten
Melek C
MC
Arkan
Günter
G
Schneider
Roland M
RM
Schmid
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D020672:I-kappa B Proteins / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012772:Shock, Septic / Q000517:prevention & control; D051996:Transcription Factor RelA / Q000502:physiology; D014158:Transcription, Genetic
D016207:Cytokines; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051996:Transcription Factor RelA