title: Transcriptional and post-transcriptional regulation of IκB-ζ upon engagement of the BCR, TLRs and FcγR.
abstract: IκB-ζ is a nuclear IκB protein robustly induced in macrophages and fibroblasts upon TLR or IL-1R stimulation. IκB-ζ associates with NF-κB in the cell nucleus and is essential for the induction of a subset of secondary response genes represented by IL-6. Here, we analyzed induction of IκB-ζ in mouse B cells and found that IκB-ζ is induced by BCR or TLR stimulation. Similar to TLR stimulation, BCR stimulation elicited NF-κB-mediated transcriptional activation and mRNA stabilization of IκB-ζ via a cis-element in IκB-ζ mRNA. Proteasome inhibitors inhibited transcriptional activation but not post-transcriptional activation, indicating independency of the two signals. Co-stimulation of the BCR and TLR9 or TLR7, but not TLR2/1, synergistically induced IκB-ζ. Co-engagement of inhibitory Fcγ receptor suppressed BCR-mediated IκB-ζ expression but not that induced by TLR stimulation alone or co-stimulation of TLR and the BCR. The PI3K inhibitor LY294002 inhibited BCR-mediated, but not TLR-mediated, induction of IκB-ζ, consistent with the role of PI3K in BCR signaling and its suppression by FcγR. Analysis of IκB-ζ-deficient B cells demonstrated that IκB-ζ was essential upon stimulation of BCR or TLR for the expression of several genes including IL-10 and CTLA4. IκB-ζ-deficient B cells exhibited impaired proliferation and enhanced up-regulation of CD86 following stimulation of TLR9, but not the BCR, indicating critical roles for IκB-ζ in TLR signaling in B cells. Strict regulatory mechanisms for the induction of IκB-ζ via multiple pathways and its essential function upon stimulation indicate that IκB-ζ plays an important role in B cells.
authors.affiliation: Laboratory of Cell Recognition and Response, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Fumito
authors.initials: F
authors.lastname: Hanihara
authors.forename: Yuta
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okuma
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohba
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Muta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology*; D051562:Proto-Oncogene Proteins c-bcr / Q000037:antagonists & inhibitors / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002867:Chromones; C485701:Fcgr1 protein, mouse; D009025:Morpholines; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D017452:Receptors, IgG; D051193:Toll-Like Receptors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr
keywords: NF-κB; gene induction; mRNA stability; nuclear IκB protein