The Nuclear I B Protein I BNS 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: 4.92). 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.

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    • "Macrophages phagocytose and rapidly kill such bacteria by using mechanisms that include the production of antimicrobial proteins and reactive oxygen species [31]. Intestinal macrophages have several unique characteristics, including the expression of the anti-inflammatory cytokine IL-10, both constitutively and after bacterial stimulation [32,33]. This makes intestinal macrophages non-inflammatory cells that still have the capacity to phagocytose. "
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    • "The interaction of IκBNS with other NF-κB family members is not entirely clear. It was shown that overexpressed IκBNS predominantly interacts with p50 but not p65 in RAW264.7 macrophages [79]. However, pulldown experiments using GST-IκBNS and protein extracts from stimulated N15 TCR transgenic thymocytes demonstrated binding to cytoplasmic and nuclear p50 as well as nuclear p52, p65, RelB and c-Rel [78]. "
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    ABSTRACT: Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning.
    Cell Communication and Signaling 04/2013; 11(1). DOI:10.1186/1478-811X-11-23 · 3.38 Impact Factor
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    • "These cells act as the first line of defense protecting the highly exposed mucosa from harmful pathogens, removing dead cells and debris, and modulating the local inflammatory response (Smith et al., 2005; Varol et al., 2010; Mowat and Bain, 2011). Unlike other tissue macrophages, upon activation, for instance by certain Toll-like receptor (TLR) ligands, intestinal macrophages do not express high levels of co-stimulatory molecules nor do they secrete pro-inflammatory cytokines (Rogler et al., 1998; Hirotani et al., 2005; Uematsu et al., 2006; Mowat and Bain, 2011; Smith et al., 2011). Rather, they produce anti-inflammatory mediators such as IL-10 and prostaglandin E2 that restrict the local immune response (Mowat and Bain, 2011). "
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