A novel role for IkappaBzeta in the regulation of IFNgamma production.
IkappaBzeta is a novel member of the IkappaB family of NFkappaB regulators, which modulates NFkappaB activity in the nucleus, rather than controlling its nuclear translocation. IkappaBzeta is specifically induced by IL-1beta and several TLR ligands and positively regulates NFkappaB-mediated transcription of genes such as IL-6 and NGAL as an NFkappaB binding co-factor. We recently reported that the IL-1 family cytokines, IL-1beta and IL-18, strongly synergize with TNFalpha for IFNgamma production in KG-1 cells, whereas the same cytokines alone have minimal effects on IFNgamma production. Given the striking similarities between the IL-1R and IL-18R signaling pathways we hypothesized that a common signaling event or gene product downstream of these receptors is responsible for the observed synergy. We investigated IkappaBzeta protein expression in KG-1 cells upon stimulation with IL-1beta, IL-18 and TNFalpha. Our results demonstrated that IL-18, as well as IL-1beta, induced moderate IkappaBzeta expression in KG-1 cells. However, TNFalpha synergized with IL-1beta and IL-18, whereas by itself it had a minimal effect on IkappaBzeta expression. NFkappaB inhibition resulted in decreased IL-1beta/IL-18/TNFalpha-stimulated IFNgamma release. Moreover, silencing of IkappaBzeta expression led to a specific decrease in IFNgamma production. Overall, our data suggests that IkappaBzeta positively regulates NFkappaB-mediated IFNgamma production in KG-1 cells.
Raices
Raquel M
RM
The Ohio State University, Davis Heart and Lung Research Institute, Columbus, Ohio, USA.
Kannan
Yashaswini
Y
Bellamkonda-Athmaram
Vedavathi
V
Seshadri
Sudarshan
S
Wang
Huating
H
Guttridge
Denis C
DC
Wewers
Mark D
MD
D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins; D007371:Interferon-gamma / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000502:physiology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering
D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D007371:Interferon-gamma
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