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


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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    • "The focus of this work was to analyze the expression of the nonclassical NF-B regulators, IBNS and Bcl-3, not previously reported expressed in the uterus along the estrous cycle. These molecules have been reported participating in the regulation of NF-B activity in the nucleus of several cells, blocking the expression of IL-6 and TNF-(Hirotani et al., 2005; Kuwata et al., 2003). It is clear that the expression of proinflammatory cytokines behaves oscillatory during the estrous cycle, but the mechanisms of such regulation still remain undescribed. "
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    ABSTRACT: The dynamic regulation of NF-κB activity in the uterus maintains a favorable environment of cytokines necessary to prepare for pregnancy throughout the estrous cycle. Recently, the mechanisms that directly regulate the NF-κB transcriptional activity in different tissues are of growing interest. IκBNS and BCL-3 are negative nuclear regulators of NF-κB activity that regulate IL-6 and TNF-α transcription, respectively. Both cytokines have been described as important factors in the remodeling of uterus for blastocyst implantation. In this work we analyzed in ICR mice the mRNA expression and protein production profile of IL-6, TNF-α, and their correspondent negative transcription regulators IκBNS or BCL-3 using real-time PCR, western blot and immunochemistry. We found that the expression of TNF-α and IL-6 was oscillatory along the estrous cycle, and its low expression coincided with the presence of BCL-3 and IκBNS, and vice versa, when the presence of the regulators was subtle, the expression of TNF-α and IL-6 was exacerbated. When we compared the production of TNF-α and IL-6 in the different estrous stages relating with diestrus we found that at estrus there is an important increase of the cytokines (p<0.05) decreasing at metestrus to reach the basal expression at diestrus. In the immunochemistry analysis we found that at diestrus BCL-3 is distributed all over the tissue with a barely detected TNF-α, but on the contrary, at estrus the expression of BCL-3 is not detected with TNF-α clearly observable along the tissue; the same phenomenon occur in the analysis of IκBNS and IL-6. With that evidence we suggest that the expression of TNF-α and IL-6 might be regulated through NF-κB nuclear regulators BCL-3 and IκBNS in the uterus of mice as has been demonstrated in other systems.
    Molecular Immunology 10/2015; 68(2). DOI:10.1016/j.molimm.2015.09.020 · 2.97 Impact Factor
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    • "Also, the abundant anti-oxidative mechanisms displayed by resident macrophages dampen the ROS-induced NLRP3 activation and the consequent release of inflammatory mediators [50]. The abundant presence of IL-10 [51] and transforming growth factor (TGF)-β [52] in the lamina propria of the healthy mucosae are also important drivers of macrophage hyporesponsiveness. Interestingly, certain chemokine receptors such as CCR5 and CXCR4 are differentially expressed in human mucosal macrophages during steady state. "
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    ABSTRACT: The epithelial layers that line the human gut and airways have evolved into tightly regulated mechanical and functional tissue barriers, the mucosae, which have to cope with unrelenting exposure to food-and airborne contaminants. In these barriers, immune cells play a major defensive role. This review describes the most important cellular and molecular mechanisms of mucosal leukocytes during homeostasis and physiological inflammation with a major focus on innate immunity (i.e. the immediate response against potential invaders). In homeostasis, a well-defined mucus layer and the epithelial layer hinder microbes from entering the underlying tissue. In addition, mucosal macrophages are patrolling scavengers with high phagocytic capacity, but their ability to mount an inflammatory response is down-regulated. Innate lymphoid cells also have an important role in maintaining a healthy mucosa. However, if bacteria overcome the barrier they cause an inflammatory reaction aimed at eliminating the threat and re-establishing tissue homeostasis. During the inflammatory response, tissue-resident immune cells become activated and promote the recruitment of monocytes and other leukocytes from the blood to the site of inflammation. The reaction evolves the contribution of mononuclear phagocytes, mast cells, neutrophils and ILCs until the infection is eliminated, tissue damage repaired and homeostasis re-established.
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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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    ABSTRACT: It is increasingly clear that the interaction between host and microbiome profoundly affects health. There are 10 times more bacteria in and on our bodies than the total of our own cells, and the human intestine contains approximately 100 trillion bacteria. Interrogation of microbial communities by using classic microbiology techniques offers a very restricted view of these communities, allowing us to see only what we can grow in isolation. However, recent advances in sequencing technologies have greatly facilitated systematic and comprehensive studies of the role of the microbiome in human health and disease. Comprehensive understanding of our microbiome will enhance understanding of disease pathogenesis, which in turn may lead to rationally targeted therapy for a number of conditions, including autoimmunity.
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