The Nuclear IκB Protein IκBNS Selectively Inhibits Lipopolysaccharide-Induced IL-6 Production in Macrophages of the Colonic Lamina Propria

Department of Host Defense, Research Institute for Microbial Diseases, Graduate School of Medicine, Osaka University, Osaka, Japan.
The Journal of Immunology (Impact Factor: 5.36). 04/2005; 174(6):3650-7. DOI: 10.4049/jimmunol.174.6.3650
Source: PubMed

ABSTRACT Macrophages play an important role in the pathogenesis of chronic colitis. However, it remains unknown how macrophages residing in the colonic lamina propria are regulated. We characterized colonic lamina proprial CD11b-positive cells (CLPMphi). CLPMphi of wild-type mice, but not IL-10-deficient mice, displayed hyporesponsiveness to TLR stimulation in terms of cytokine production and costimulatory molecule expression. We compared CLPMphi gene expression profiles of wild-type mice with IL-10-deficient mice, and identified genes that are selectively expressed in wild-type CLPMphi. These genes included nuclear IkappaB proteins such as Bcl-3 and IkappaBNS. Because Bcl-3 has been shown to specifically inhibit LPS-induced TNF-alpha production, we analyzed the role of IkappaBNS in macrophages. Lentiviral introduction of IkappaBNS resulted in impaired LPS-induced IL-6 production, but not TNF-alpha production in the murine macrophage cell line RAW264.7. IkappaBNS expression led to constitutive and intense DNA binding of NF-kappaB p50/p50 homodimers. IkappaBNS was recruited to the IL-6 promoter, but not to the TNF-alpha promoter, together with p50. Furthermore, small interference RNA-mediated reduction in IkappaBNS expression in RAW264.7 cells resulted in increased LPS-induced production of IL-6, but not TNF-alpha. Thus, IkappaBNS selectively suppresses LPS-induced IL-6 production in macrophages. This study established that nuclear IkappaB proteins differentially regulate LPS-induced inflammatory cytokine production in macrophages.

  • Source
    • "Unlike typical IkB proteins, IkBNS overexpression only marginally inhibits NF-kB (Fiorini et al. 2002). Like BCL-3, IkBNS is strongly induced by the anti-inflammatory cytokine IL-10 and appears to mediate some of the repressive effects of IL-10 on proinflammatory cytokine production during TLR stimulation (Hirotani et al. 2005). Given that IkBNS shows a preference for binding to p50 (Fiorini et al. 2002), it has been assumed that it inhibits NF-kB-dependent proinflammatory gene expression by stabilizing p50 homodimers at kB sites. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.
    Genes & development 02/2012; 26(3):203-34. DOI:10.1101/gad.183434.111 · 12.64 Impact Factor
  • Source
    • "It was reported that IjBNS and Bcl-3 inhibit the transcription of IL-6 and TNFa, respectively [15] [16]. Unlike ''classical'' IjB proteins, IjBNS and Bcl-3 exert their roles in the nucleus to stabilize DNAbound p50 homo-dimer, which is known to be a transcriptional inactive complex, resulting in the prevention of RelA-containing active dimer recruitment to the promoter of inflammatory cytokine genes [15] [16]. In our preliminary experiment using chromatin immuno-precipitation technique, the forced expression of IjBL reduced the recruitment of RelA on the IL-6 and TNFa promoters (unpublished data), assuming that IjBL regulates cytokine gene expression by controlling the binding of active NF-jB complex to DNA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that IκBL prevents experimental autoimmune arthritis. The molecular mechanism, however, still remains unclear. In contrast to four splicing-isoforms of IκBL in human, two isoforms were identified in mouse. The major isoform IκBL-α(S) suppressed LPS-induced NF-κB activation and transcription of TNFα and IL-6, but not IL-1β. The suppressive activity required the nuclear localization signal and the ankyrin repeat domain of IκBL. IκBL did not affect the nuclear translocation of the NF-κB dimer. These findings point to IκBL as being a novel member of the nuclear IκB family, which functions in the nucleus and controls various inflammatory responses including autoimmune arthritis.
    FEBS letters 11/2011; 585(22):3577-81. DOI:10.1016/j.febslet.2011.10.024 · 3.34 Impact Factor
  • Source
    • "Further studies demonstrated that IBNS -/-mice showed a reduced TCR-dependent proliferation of T-cells, associated with a reduction in IL-2 levels [101]. However in macrophages treated with LPS, IBNS is recruited to the il-6 promoter together with p50 correlating with its transcriptional suppression [102]. In agreement with these data, IBNS -/-mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation [103]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The NF-κB signalling pathway regulates many different biological processes from the cellular level to the whole organism. The majority of these functions are completely dependent on the activation of the cytoplasmic IKK kinase complex that leads to IκB degradation and results in the nuclear translocation of specific NF-κB dimers, which, in general, act as transcription factors. Although this is a well-established mechanism of action, several publications have now demonstrated that some members of this pathway display additional functions in the nucleus as regulators of NF-κB-dependent and independent gene expression. In this review, we compiled and put in context most of the data concerning specific nuclear roles for IKK and IκB proteins.
    American Journal of Cancer Research 01/2011; 1(4):446-59. · 3.97 Impact Factor
Show more


1 Download
Available from