scholarly journals “Re-educating” tumor-associated macrophages by targeting NF-κB

2008 ◽  
Vol 205 (6) ◽  
pp. 1261-1268 ◽  
Author(s):  
Thorsten Hagemann ◽  
Toby Lawrence ◽  
Iain McNeish ◽  
Kellie A. Charles ◽  
Hagen Kulbe ◽  
...  
Keyword(s):  
Nk Cell ◽  
Nuclear Factor Κb ◽  
Tumor Associated Macrophages ◽  
Tumoricidal Activity ◽  
Macrophage Population ◽  
Cell Recruitment ◽  
Histocompatibility Complex ◽  
Iκb Kinase ◽  
Classically Activated

The nuclear factor κB (NF-κB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-κB in cancer in maintaining the immunosuppressive phenotype of tumor-associated macrophages (TAMs). We show that macrophages are polarized via interleukin (IL)-1R and MyD88 to an immunosuppressive “alternative” phenotype that requires IκB kinase β–mediated NF-κB activation. When NF-κB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a “classically” activated phenotype; IL-12high, major histocompatibility complex IIhigh, but IL-10low and arginase-1low. Targeting NF-κB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12–dependent NK cell recruitment. We provide a rationale for manipulating the phenotype of the abundant macrophage population already located within the tumor microenvironment; the potential to “re-educate” the tumor-promoting macrophage population may prove an effective and novel therapeutic approach for cancer that complements existing therapies.

scholarly journals TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

2009 ◽  
Vol 201 (2) ◽  
pp. 185-197 ◽  
Author(s):  
Marina C Muñoz ◽  
Jorge F Giani ◽  
Marcos A Mayer ◽  
Jorge E Toblli ◽  
Daniel Turyn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Genetic Model ◽  
Glycogen Synthase ◽  
Resistance Mechanism ◽  
Nuclear Factor Κb ◽  
Zucker Rats ◽  
Ang Ii ◽  
Iκb Kinase

The IκB kinase-β (IKK-β)/nuclear factor-κB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3β. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

scholarly journals Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Science ◽  
2018 ◽  
Vol 362 (6416) ◽  
pp. 834-839 ◽  
Author(s):  
Torkild Visnes ◽  
Armando Cázares-Körner ◽  
Wenjing Hao ◽  
Olov Wallner ◽  
Geoffrey Masuyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Nuclear Factor Κb ◽  
Cell Recruitment ◽  
Inflammatory Conditions ◽  
Molecule Inhibitor ◽  
Proinflammatory Gene ◽  
Factor Α ◽  
Proinflammatory Gene Expression

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

Expression of Major Histocompatibility Complex Class I-Related Chain (MIC) on Fresh and Cloned Myeloma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2465-2465
Author(s):  
Masashi Okamoto ◽  
Tohru Inaba ◽  
Sonoko Nakano ◽  
Kyoko Namura ◽  
Noriko Yamada ◽  
...  
Keyword(s):  
Cell Lines ◽  
Nk Cell ◽  
Myeloma Cell ◽  
Rt Pcr ◽  
Myeloma Cells ◽  
Ifn Alpha ◽  
Histocompatibility Complex ◽  
Nk Cell Cytotoxicity ◽  
Nk Cytotoxicity

Abstract Introduction: Major histocompatibility complex class-I related chain (MIC) is a ligand for NKG2D, one of the activating NK receptor. It is expressed on various cancerous cells, and mediates NK cytolysis. Myeloma cells may be susceptible to immune therapy because interferon (IFN)-alpha or thalidomide are effective for a part of myeloma patients. It is also reported that one myeloma cell line is susceptible to NK cytolysis, but another lines are not, and this difference is not depend on its KIR incompatibility. We therefore examined the expression of MIC on myeloma cells, and its role on NK cell cytotoxicity. Method: MIC expression was examined on two myeloma cell lines, U266 and RPMI8226, and fresh myeloma cells by flow cytometry (FCM) and reverse transcript polymerase chain reaction (RT-PCR). Modulation of MIC expression on these cell lines and fresh myeloma cells by the addition of various concentration of the drugs such as IFN-alpha, thalidomide, all-trans retinoic acid (ATRA), dexamethasone, and incadronate was examined by FCM and RT-PCR. The relationship between MIC expression and NK cytolysis was examine by 51Cr release assay. Result: MIC was highly expressed on these two cell lines. MIC mRNA was also detected by RT-PCR in both cell lines. IFN-alpha, thalidomide, ATRA, incadronate and dexamethasone are known to be effective for MM in vivo or in vitro, we therefore examined the effect of these drugs on the expression of MIC on two myeloma cell lines. The cell lines were treated with or without these drugs at various concentrations, and then subjected to FCM. MIC expression was not changed after treatment of thalidomide, incadronate and dexamethasone. But unexpectedly, it was down-regulated by IFN-alpha and ATRA dose-dependently on both cell lines. To examine whether MIC expression on myeloma cell lines is involved in their susceptibility to NK cells, NK cell cytotoxicity against these cell lines was analyzed by 51Cr releasing assay. A substantial cytolysis was detected in U266 cells, while RPMI8226 did not show any relevant cytolysis, though the cell line express high level of MIC. Furthermore NK cytotoxicity was not inhibited by the addition of anti-MIC antibody. Then we examined the effect of IFN-alpha on the NK cytotoxicity, because IFN-alpha down-regulated the expression of MIC on myeloma cell lines. However, NK cytotoxicity was also induced by IFN-alpha in both cell lines. To examine whether MIC is expressed on fresh myeloma cells and is involved in the effect of the various drugs against myeloma cells, fresh samples from 12 MM patients were examined on the expression of MIC using two-color flow cytometric analysis. MIC was expressed on myeloma cells in one of 12 patients examined. The treatment with IFN-alpha, thalidomide and ATRA did not up-regulated the expression of MIC in all samples. Conclusion: MIC is expressed on myeloma cell lines, but rarely expressed on fresh myelma cells. The reason of the discrepancy of MIC expression between fresh and cloned myeloma cells may be that myeloma cells are killed by host NK cells in vivo, provided the cells express MIC. In case myeloma cells express MIC in vivo, it may be that the molecule is not recognized by NKG2D on the NK cell.

scholarly journals p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells

2013 ◽  
Vol 210 (10) ◽  
pp. 2057-2069 ◽  
Author(s):  
Alexandre Iannello ◽  
Thornton W. Thompson ◽  
Michele Ardolino ◽  
Scott W. Lowe ◽  
David H. Raulet
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Cellular Senescence ◽  
Nk Cell ◽  
Liver Carcinoma ◽  
Chemokine Production ◽  
P53 Expression ◽  
Cell Recruitment ◽  
Ligand Expression

The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis. Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors. The elimination of senescent tumor cells is dependent on NKG2D. Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells. Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells. Antibody-mediated neutralization of CCL2, but not CCL3, CCL4 or CCL5, prevented NK cell recruitment to the senescent tumors and reduced their elimination. Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells.

scholarly journals Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype

2020 ◽  
Vol 8 (1) ◽  
pp. e000339 ◽  
Author(s):  
Hongliang Dong ◽  
Yueyao Yang ◽  
Chenhui Gao ◽  
Hehe Sun ◽  
Hongmin Wang ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Suppressor Cells ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Tumor Associated Macrophages ◽  
Antitumor Effects ◽  
Tumoricidal Activity ◽  
Arginase 1

BackgroundTumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy.MethodsA mouse IgG1(kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models.ResultsThrough coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues.ConclusionsLTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.

scholarly journals IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss

2005 ◽  
Vol 201 (10) ◽  
pp. 1677-1687 ◽  
Author(s):  
Maria Grazia Ruocco ◽  
Shin Maeda ◽  
Jin Mo Park ◽  
Toby Lawrence ◽  
Li-Chung Hsu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Osteoclast Survival

Transcription factor, nuclear factor κB (NF-κB), is required for osteoclast formation in vivo and mice lacking both of the NF-κB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IκB kinase (IKK) complex that mediate NF-κB activation, IKKα and IKKβ, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKβ subunit as a transducer of signals from receptor activator of NF-κB (RANK) to NF-κB. Although IKKα is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKβ is required for osteoclastogenesis in vitro and in vivo. IKKβ also protects osteoclasts and their progenitors from tumor necrosis factor α–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

scholarly journals Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes

2005 ◽  
Vol 202 (5) ◽  
pp. 687-696 ◽  
Author(s):  
Thomas G. Diacovo ◽  
Amanda L. Blasius ◽  
Tak W. Mak ◽  
Marina Cella ◽  
Marco Colonna
Keyword(s):  
Lymph Nodes ◽  
Nk Cell ◽  
High Endothelial Venules ◽  
Cell Recruitment ◽  
Cell Responses ◽  
Peripheral Lymph ◽  
Chemokine Receptor Ccr5 ◽  
Gain Access ◽  
Receptor Ccr5

Natural interferon-producing cells (IPCs) are found in peripheral lymph nodes (PLNs), where they support NK cell, T cell, and B cell responses to pathogens. However, their route of entry and the adhesive mechanisms used to gain access to PLNs remain poorly defined. We report that IPCs can enter PLNs via a hematogenous route, which involves a multistep adhesive process, and that transmigration is enhanced by inflammation. Results indicate that L-selectin on IPCs is required for efficient attachment and rolling on high endothelial venules in vivo in both nonstimulated and inflamed PLNs. IPCs, however, also possess functional ligands for E-selectin that contribute to this process only in the latter case. In conjunction with selectin-mediated adhesion, both β1- and β2-integrins participate in IPC attachment to the inflamed vessel wall, whereas chemotaxis relies in part on the chemokine receptor CCR5. Identification of the adhesive machinery required for IPC trafficking into PLNs may provide opportunities to regulate immune responses reliant on the activity of these cells.

Regulation of IκB kinase and NF-κB in contracting adult rat skeletal muscle

2005 ◽  
Vol 289 (4) ◽  
pp. C794-C801 ◽  
Author(s):  
Richard C. Ho ◽  
Michael F. Hirshman ◽  
Yangfeng Li ◽  
Dongsheng Cai ◽  
Jocelyn R. Farmer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Time Course ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Muscle Gene Expression ◽  
Iκb Kinase ◽  
Gastrocnemius Muscles

Nuclear factor-κB (NF-κB) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-κB is activated through the phosphorylation of its inhibitor, IκB, by the IκB kinase (IKK) complex. Physical exercise elicits changes in skeletal muscle gene expression, yet signaling cascades and transcription factors involved remain largely unknown. To determine whether NF-κB signaling is regulated by exercise in vivo, rats were run on a motorized treadmill for 5–60 min. Exercise resulted in up to twofold increases in IKKα/β phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-κB activity increased 50% 1–3 h after 60 min of treadmill exercise, returning to baseline by 5 h. Contraction of isolated extensor digitorum longus muscles in vitro increased IKKα/β phosphorylation sevenfold and this was accompanied by a parallel increase in IκBα phosphorylation. Additional kinases that are activated by exercise include p38, extracellular-signal regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK). Inhibitors of p38 (SB-203580) and ERK (U-0126) blunted contraction-mediated IKK phosphorylation by 39 ± 4% ( P = 0.06) and 35 ± 10% ( P = 0.09), respectively, and in combination by 76 ± 5% ( P < 0.05), suggesting that these kinases might influence the activation of IKK and NF-κB during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-κB activity. In conclusion, acute submaximal exercise transiently stimulates NF-κB signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors.

Activation of NF-κB by hepatitis B virus X protein through an IκB kinase-independent mechanism

2001 ◽  
Vol 280 (4) ◽  
pp. G669-G677 ◽  
Author(s):  
Nicole H. Purcell ◽  
Chenfei Yu ◽  
Daoyao He ◽  
Jialing Xiang ◽  
Nir Paran ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Phorbol Esters ◽  
Nuclear Translocation ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Iκb Kinase ◽  
Human T Cell ◽  
B Virus

pX, the hepatitis B virus-encoded transcription coactivator, is involved in viral infection in vivo. pX stimulates the activity of several transcription factors including nuclear factor-κB (NF-κB), but the mechanism of activation is poorly understood. The IκB kinase complex (IKK) mediates activation of NF-κB in response to various extracellular stimuli, including inflammatory cytokines like tumor necrosis factor and interleukin 1, human T cell lymphoma virus 1 Tax protein, and tumor promoters like phorbol esters. It is not known whether IKK also mediates activation of NF-κB by pX. Here we report that IKK was not essential for activation of NF-κB by pX. Expression of pX resulted in the degradation of IκBα in the absence of its phosphorylation at Ser32and Ser36residues. Although pX stimulated the activity of cotransfected IKK-β when it was overexpressed, it failed to activate endogenous IKK. Furthermore, expression of pX stimulated NF-κB nuclear translocation and transcriptional activity in IKK-γ-null fibroblast 5R cells. Our data indicate that pX stimulates NF-κB activity through a mechanism that is dependent on IκBα degradation but not on IKK activation.

scholarly journals Tumorigenicity conferred to lymphoma mutant by major histocompatibility complex-encoded transporter gene.

1993 ◽  
Vol 177 (1) ◽  
pp. 201-205 ◽  
Author(s):  
L Franksson ◽  
E George ◽  
S Powis ◽  
G Butcher ◽  
J Howard ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

Presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules requires MHC-encoded molecules of the adenosine triphosphate binding cassette (ABC) family. Defects in these proteins represent a potential risk, since they are essential links in the machinery of T cell-mediated surveillance which continuously scrutinizes peptide samples of cellular proteins. Nevertheless, transfection of the mouse lymphoma mutant RMA-S with the rat ABC gene mtp2a (homologue to mouse HAM2 and human RING11), commonly termed TAP-2 genes, led to a marked increase in tumor outgrowth potential in vivo. This occurred despite restored antigen presentation and sensitivity to cytotoxic T lymphocytes, and was found to be due to escape from natural killer (NK) cell-mediated rejection. It has previously been proposed that adequate expression of self-MHC class I is one important mechanism to avoid elimination by NK cells. Our data argue that a defect in the machinery responsible for processing and loading of peptides into MHC class I molecules is sufficient to render cells sensitive to elimination by NK cells. The latter thus appear to function as a surveillance of the peptide surveillance machinery.

Sign in / Sign up

Export Citation Format

Share Document