scholarly journals IκB Kinase Signaling Is Essential for Maintenance of Mature B Cells

2002 ◽  
Vol 196 (6) ◽  
pp. 743-752 ◽  
Author(s):  
Manolis Pasparakis ◽  
Marc Schmidt-Supprian ◽  
Klaus Rajewsky
Keyword(s):  
B Cells ◽  
Regulatory Subunit ◽  
Cellular Survival ◽  
Adult Mice ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Conditional Gene Targeting ◽  
B Lineage ◽  
Deficient Mice

Nuclear factor (NF)-κB proteins play crucial roles in immune responses and cellular survival. Activation of NF-κB is mediated by the IκB kinase (IKK) complex, which is composed of two kinases, IKK1 and IKK2, and a regulatory subunit termed NF-κB essential modulator (NEMO). IKK2- and NEMO-deficient mice die at early embryonic stages. We therefore used conditional gene targeting to evaluate the role of these proteins in B cells in adult mice. B lineage–specific disruption of either IKK signaling by deletion of NEMO, or of IKK2-specific signals by ablation of IKK2 activity leads to the disappearance of mature B lymphocytes. We conclude that maintenance of mature B cells depends on IKK-mediated activation of NF-κB.

scholarly journals Osteopontin drives KRAS-mutant lung adenocarcinoma

2019 ◽  
Vol 41 (8) ◽  
pp. 1134-1144 ◽  
Author(s):  
Ioanna Giopanou ◽  
Nikolaos I Kanellakis ◽  
Anastasios D Giannou ◽  
Ioannis Lilis ◽  
Antonia Marazioti ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Airway Epithelial ◽  
Poor Survival ◽  
Cellular Survival ◽  
Tobacco Carcinogen ◽  
Lung Epithelial ◽  
Secreted Phosphoprotein 1 ◽  
Deficient Mice ◽  
Important Therapeutic Target

Abstract Increased expression of osteopontin (secreted phosphoprotein 1, SPP1) is associated with aggressive human lung adenocarcinoma (LADC), but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced LADC. We combined mouse models of tobacco carcinogen-induced LADC, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis. Co-expression of Spp1 and mutant KrasG12C in benign cells was employed to investigate SPP1/KRAS interactions in oncogenesis. Finally, intratracheal adenovirus encoding Cre recombinase was delivered to LSL.KRASG12D mice lacking endogenous or overexpressing transgenic Spp1 alleles. SPP1 was overexpressed in experimental and human LADC and portended poor survival. In response to two different smoke carcinogens, Spp1-deficient mice developed fewer and smaller LADC with decreased cellular survival and angiogenesis. Both lung epithelial- and macrophage-secreted SPP1 drove tumor-associated inflammation, while epithelial SPP1 promoted early tumorigenesis by fostering the survival of KRAS-mutated cells. Finally, loss and overexpression of Spp1 was, respectively, protective and deleterious for mice harboring KRASG12D-driven LADC. Our data support that SPP1 is functionally involved in early stages of airway epithelial carcinogenesis driven by smoking and mutant KRAS and may present an important therapeutic target.

scholarly journals Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα

2001 ◽  
Vol 21 (4) ◽  
pp. 1024-1035 ◽  
Author(s):  
Vigo Heissmeyer ◽  
Daniel Krappmann ◽  
Eunice N. Hatada ◽  
Claus Scheidereit
Keyword(s):  
B Cells ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Docking Site ◽  
Death Domain ◽  
Relevant Model ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Processing Product ◽  
Destruction Box

ABSTRACT p105 (NFKB1) acts in a dual way as a cytoplasmic IκB molecule and as the source of the NF-κB p50 subunit upon processing. p105 can form various heterodimers with other NF-κB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IκB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKβ phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGΨ motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IκBα, -β, and -ɛ. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules βTrCP1 and βTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKγ, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.

scholarly journals Antibody Is Critical for the Clearance of Murine Norovirus Infection

2008 ◽  
Vol 82 (13) ◽  
pp. 6610-6617 ◽  
Author(s):  
Karen A. Chachu ◽  
David W. Strong ◽  
Anna D. LoBue ◽  
Christiane E. Wobus ◽  
Ralph S. Baric ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Murine Norovirus ◽  
Wild Type ◽  
Human Norovirus ◽  
Mucosal Infection ◽  
Antibody Levels ◽  
Deficient Mice ◽  
Immune Antibody

ABSTRACT Human noroviruses cause more than 90% of epidemic nonbacterial gastroenteritis. However, the role of B cells and antibody in the immune response to noroviruses is unclear. Previous studies have demonstrated that human norovirus specific antibody levels increase upon infection, but they may not be protective against infection. In this report, we used murine norovirus (MNV), an enteric norovirus, as a model to determine the importance of norovirus specific B cells and immune antibody in clearance of norovirus infection. We show here that mice genetically deficient in B cells failed to clear primary MNV infection as effectively as wild-type mice. In addition, adoptively transferred immune splenocytes derived from B-cell-deficient mice or antibody production-deficient mice were unable to efficiently clear persistent MNV infection in RAG1−/− mice. Further, adoptive transfer of either polyclonal anti-MNV serum or neutralizing anti-MNV monoclonal antibodies was sufficient to reduce the level of MNV infection both systemically and in the intestine. Together, these data demonstrate that antibody plays an important role in the clearance of MNV and that immunoglobulin G anti-norovirus antibody can play an important role in clearing mucosal infection.

scholarly journals Interleukin 6 is essential for in vivo development of B lineage neoplasms.

1995 ◽  
Vol 182 (1) ◽  
pp. 243-248 ◽  
Author(s):  
D M Hilbert ◽  
M Kopf ◽  
B A Mock ◽  
G Köhler ◽  
S Rudikoff
Keyword(s):  
Plasma Cell ◽  
Plasma Cells ◽  
Tumor Development ◽  
Selective Pressures ◽  
B Lineage ◽  
Deficient Mice ◽  
Human B Cell

Interleukin (IL) 6 has been suggested to be the major cytokine responsible for proliferation of neoplastic plasma cells in both human myeloma and mouse plasmacytoma. Much of the evidence supporting this suggestion is derived from in vitro studies in which the survival or proliferation of some plasma cell tumors has been found to be IL-6 dependent. However, it remains unclear whether this dependency is the consequence of in vivo or in vitro selective pressures that preferentially expand IL-6-responsive tumor cells, or whether it reflects a critical in vivo role for IL-6 in plasma cell neoplasia. To address this question, we have attempted to induce plasma cell tumors in normal mice and in IL-6-deficient mice generated by introduction of a germline-encoded null mutation in the IL-6 gene. The results demonstrate that mice homozygous (+/+) or heterozygous (+/-) for the wild-type IL-6 allele yield the expected incidences of plasma cell tumors. In contrast, mice homozygous for the IL-6-null allele (-/-) are completely resistant to plasma cell tumor development. These studies define the essential role of IL-6 in the development of B lineage tumors in vivo and provide experimental support for continued efforts to modulate this cytokine in the treatment of appropriate human B cell malignancies.

IL-7 mediates Ebf-1–dependent lineage restriction in early lymphoid progenitors

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1283-1290 ◽  
Author(s):  
Panagiotis Tsapogas ◽  
Sasan Zandi ◽  
Josefine Åhsberg ◽  
Jenny Zetterblad ◽  
Eva Welinder ◽  
...  
Keyword(s):  
Normal Development ◽  
Cell Potential ◽  
Lymphoid Development ◽  
Adult Mice ◽  
Lymphoid Progenitors ◽  
The Common ◽  
B Lineage ◽  
Cell Commitment ◽  
A Minor ◽  
Deficient Mice

Abstract Deficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D− multipotent CLPs, the formation of the lineage restricted LY6D+ CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D+ CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D+ cells develop in Ebf-1–deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D+ CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.

scholarly journals Crucial Role of Tumor Necrosis Factor Receptor 1 Expression on Nonhematopoietic Cells for B Cell Localization within the Splenic White Pulp

1998 ◽  
Vol 187 (4) ◽  
pp. 469-477 ◽  
Author(s):  
Maria Tkachuk ◽  
Stephan Bolliger ◽  
Bernhard Ryffel ◽  
Gerd Pluschke ◽  
Theresa A. Banks ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Plasma Cells ◽  
Tumor Necrosis Factor Receptor ◽  
White Pulp ◽  
Splenic White Pulp ◽  
Initial Activation ◽  
Deficient Mice ◽  
Necrosis Factor

During immune responses the initial activation of B cells takes place in T cell zones of periarteriolar lymphoid sheaths (PALS) of the splenic white pulp. After initial activation, B cells migrate into the primary follicles and, in association with follicular dendritic cells (FDCs), undergo clonal expansion and differentiation giving rise to germinal centers (GCs). Peanut agglutinin binding (PNA+) cells of the GC differentiate further into memory or plasma cells. Here we report that in tumor necrosis factor receptor 1–deficient mice (TNFR1−/−), the location of B cells was altered and that plasma cells were abnormally distributed in the splenic PALS. In contrast to lymphotoxin α–deficient mice (LTα−/−), bone marrow or fetal liver transplantation did not correct the abnormal organization of the spleen, location of B cells, the lack of an FDC network, nor the antibody response in TNFR1−/− mice. These results argue for a crucial role of TNFR1 expression on nonhematopoietic cells for the maintenance of the splenic architecture and proper B cell location. In addition, the lack in development of an FDC network after adoptive transfer suggests that either FDCs are not of bone marrow origin or that they depend on signals from nonhematopoietic cells for maturation.

scholarly journals Are B Lymphocytes of Importance in Severe Staphylococcus aureus Infections?

2000 ◽  
Vol 68 (5) ◽  
pp. 2431-2434 ◽  
Author(s):  
Inger Gjertsson ◽  
Olof Hörnquist Hultgren ◽  
Martin Stenson ◽  
Rikard Holmdahl ◽  
Andrzej Tarkowski
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Wild Type ◽  
Toxic Shock ◽  
Toxic Shock Syndrome Toxin ◽  
Deficient Mice ◽  
Wild Type Control

ABSTRACT To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0.0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course ofS. aureus-induced septic arthritis.

scholarly journals The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

1999 ◽  
Vol 189 (11) ◽  
pp. 1839-1845 ◽  
Author(s):  
Zhi-Wei Li ◽  
Wenming Chu ◽  
Yinling Hu ◽  
Mireille Delhase ◽  
Tom Deerinck ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nuclear Factor ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

scholarly journals Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Zuqiang Wang ◽  
Hangang Chen ◽  
Qiaoyan Tan ◽  
Junlan Huang ◽  
Siru Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Current Therapies ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Deficient Mice

AbstractThe intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

scholarly journals Hepatocyte-specific NEMO deletion promotes NK/NKT cell– and TRAIL-dependent liver damage

2009 ◽  
Vol 206 (8) ◽  
pp. 1727-1737 ◽  
Author(s):  
Naiara Beraza ◽  
Yann Malato ◽  
Leif E. Sander ◽  
Malika Al-Masaoudi ◽  
Julia Freimuth ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nkt Cell ◽  
Cell Tissue ◽  
Ikk Complex

Nuclear factor κB (NF-κB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-κB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMOΔhepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMOΔhepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMOΔhepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMOΔhepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)–mediated injury. The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient−/− mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.

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