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PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.
Iwata H, Goettsch C, Sharma A, Ricchiuto P, Goh WW, Halu A, Yamada I, Yoshida H, Hara T, Wei M, Inoue N, Fukuda D, Mojcher A, Mattson PC, Barabási AL, Boothby M, Aikawa E, Singh SA, Aikawa M
(2016) Nat Commun 7: 12849
MeSH Terms: ADP-Ribosylation, Animals, Apoptosis, Atherosclerosis, Cell Survival, Coronary Artery Disease, Female, Humans, Inflammation, Interferon-gamma, Interleukin-4, Lipopolysaccharide Receptors, Macrophage Activation, Male, Mice, Mice, Inbred C57BL, Neoplasm Proteins, Phosphorylation, Plaque, Atherosclerotic, Poly(ADP-ribose) Polymerases, RAW 264.7 Cells, RNA Interference, Ribose, STAT1 Transcription Factor, THP-1 Cells
Show Abstract · Added March 14, 2018
Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9-PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.
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25 MeSH Terms
IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.
Zhang MZ, Wang X, Wang Y, Niu A, Wang S, Zou C, Harris RC
(2017) Kidney Int 91: 375-386
MeSH Terms: Acute Kidney Injury, Animals, Cell Plasticity, Dendritic Cells, Diphtheria Toxin, Disease Models, Animal, Fibrosis, Genotype, Heparin-binding EGF-like Growth Factor, Interleukin-13, Interleukin-4, Janus Kinase 3, Kidney, Macrophages, Male, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Knockout, Phenotype, Recovery of Function, Reperfusion Injury, STAT6 Transcription Factor, Signal Transduction, Time Factors
Show Abstract · Added April 26, 2017
Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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24 MeSH Terms
Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth.
Zhao G, Liu L, Peek RM, Hao X, Polk DB, Li H, Yan F
(2016) J Biol Chem 291: 20462-72
MeSH Terms: Animals, Cell Line, Tumor, ErbB Receptors, Gastrointestinal Neoplasms, Gene Expression Regulation, Neoplastic, Heparin-binding EGF-like Growth Factor, Humans, Interleukin-4, Macrophages, Peritoneal, Mice, Mice, Knockout, RAW 264.7 Cells, Transcriptional Activation
Show Abstract · Added April 6, 2017
EGF receptor (EGFR) in tumor cells serves as a tumor promoter. However, information about EGFR activation in macrophages in regulating M2 polarization and tumor development is limited. This study aimed to investigate the effects of EGFR activation in macrophages on M2 polarization and development of gastrointestinal tumors. IL-4, a cytokine to elicit M2 polarization, stimulated release of an EGFR ligand, HB-EGF, and transactivation and down-regulation of EGFR in Raw 264.7 cells and peritoneal macrophages from WT mice. Knockdown of HB-EGF in macrophages inhibited EGFR transactivation by IL-4. IL-4-stimulated STAT6 activation, Arg1 and YM1 gene expression, and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr(wa5) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr(fl/fl) LysM-Cre mice with myeloid cell-specific EGFR deletion. Chitin induced a higher level of M2 polarization in peritoneal macrophages in Egfr(fl/fl) LysM-Cre mice than that in Egfr(fl/fl) mice. Accordingly, IL-4-conditioned medium stimulated growth and epithelial-to-mesenchymal transition in gastric epithelial and colonic tumor cells, which were suppressed by that from Raw 264.7 cells with HB-EGF knockdown but promoted by that from Egfr(wa5) and Egfr(fl/fl) LysM-Cre peritoneal macrophages. Clinical assessment revealed that the number of macrophages with EGFR expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers. Thus, IL-4-stimulated HB-EGF-dependent transactivation of EGFR in macrophages may mediate inhibitory feedback for M2 polarization and HB-EGF production, thereby inhibiting gastrointestinal tumor growth.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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13 MeSH Terms
Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites.
Wan X, Thomas JW, Unanue ER
(2016) J Exp Med 213: 967-78
MeSH Terms: Animals, Antigen Presentation, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Germinal Center, Immunoglobulin Class Switching, Insulin, Interleukin-4, Islets of Langerhans, Mice, Mice, Knockout, T-Lymphocytes
Show Abstract · Added November 23, 2016
Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis.
© 2016 Wan et al.
2 Communities
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13 MeSH Terms
Targeting IL4/IL4R for the treatment of epithelial cancer metastasis.
Bankaitis KV, Fingleton B
(2015) Clin Exp Metastasis 32: 847-56
MeSH Terms: Humans, Interleukin-4, Janus Kinase 1, Neoplasms, Glandular and Epithelial, Receptors, Interleukin-4, STAT6 Transcription Factor, Signal Transduction, Tumor Microenvironment
Show Abstract · Added September 28, 2015
While progress has been made in treating primary epithelial tumors, metastatic tumors remain largely incurable and still account for 85-90 % of all cancer-related deaths. Interleukin-4 (IL4), a Th2 cytokine, and the IL4/IL4 receptor (IL4R) interaction have well defined roles in the immune system. Yet, IL4 receptors are over-expressed by many epithelial cancers and could be a promising target for metastatic tumor therapy. The IL4/IL4R signaling axis is a strong promoter of pro-metastatic phenotypes in epithelial cancer cells including enhanced migration, invasion, survival, and proliferation. The promotion of breast cancer growth specifically is also supported in part by IL4-induced glutamine metabolism, and we have shown that IL4 is also capable of inducing glucose metabolism in breast cancer cells. Importantly, there are several types of FDA approved medications for use in asthma patients that inhibit the IL4/IL4R signaling axis. However, these approved medications inhibit both the type I IL4 receptor found on immune cells, and the type II IL4 receptor that is predominantly expressed by some non-hematopoietic cells including epithelial cancer cells. This article reviews existing therapies targeting IL4, IL4R, or IL4/IL4R signaling, and recent findings guiding the creation of novel therapies that specifically inhibit the type II IL4R, while taking into consideration effects on immune cells within the tumor microenvironment. Some of these therapies are currently in clinical trials for cancer patients, and may be exploitable for the treatment of metastatic disease.
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8 MeSH Terms
Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.
Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, Washington MK, Peek RM, Belkhiri A, El-Rifai WM
(2015) Cancer 121: 4348-58
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Chemokine CXCL5, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, I-kappa B Kinase, In Vitro Techniques, Inflammation, Interleukin-1beta, Mice, Mice, Knockout, Peptides, Phosphorylation, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-4, Stomach, Stomach Neoplasms, Transcription Factor RelA, Trefoil Factor-1, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added September 28, 2015
BACKGROUND - Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.
METHODS - For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.
RESULTS - The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.
CONCLUSIONS - These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.
© 2015 American Cancer Society.
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24 MeSH Terms
CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue.
Bolus WR, Gutierrez DA, Kennedy AJ, Anderson-Baucum EK, Hasty AH
(2015) J Leukoc Biol 98: 467-77
MeSH Terms: Adipose Tissue, Animals, Cell Separation, Eosinophils, Flow Cytometry, Immunohistochemistry, Inflammation, Insulin Resistance, Interleukin-13, Interleukin-4, Interleukin-5, Macrophage Activation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Real-Time Polymerase Chain Reaction, Receptors, CCR2
Show Abstract · Added September 28, 2015
Adipose tissue (AT) inflammation during obesity is mediated by immune cells and closely correlates with systemic insulin resistance. In lean AT, eosinophils are present in low but significant numbers and capable of promoting alternative macrophage activation in an IL-4/IL-13-dependent manner. In WT mice, obesity causes the proportion of AT eosinophils to decline, concomitant with inflammation and classical activation of AT macrophages. In this study, we show that CCR2 deficiency leads to increased eosinophil accumulation in AT. Furthermore, in contrast to WT mice, the increase in eosinophils in CCR2(-/-) AT is sustained and even amplified during obesity. Interestingly, a significant portion of eosinophils is found in CLSs in AT of obese CCR2(-/-) mice, which is the first time eosinophils have been shown to localize to these inflammatory hot spots. CCR2(-/-) bone marrow precursors displayed increased expression of various key eosinophil genes during in vitro differentiation to eosinophils, suggesting a potentially altered eosinophil phenotype in the absence of CCR2. In addition, the proportion of eosinophils in AT positively correlated with local expression of Il5, a potent eosinophil stimulator. The increase in eosinophils in CCR2(-/-) mice was detected in all white fat pads analyzed and in the peritoneal cavity but not in bone marrow, blood, spleen, or liver. In AT of CCR2(-/-) mice, an increased eosinophil number positively correlated with M2-like macrophages, expression of the Treg marker Foxp3, and type 2 cytokines, Il4, Il5, and Il13. This is the first study to link CCR2 function with regulation of AT eosinophil accumulation.
© Society for Leukocyte Biology.
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19 MeSH Terms
Bombesin Preserves Goblet Cell Resistin-Like Molecule β During Parenteral Nutrition but Not Other Goblet Cell Products.
Busch RA, Heneghan AF, Pierre JF, Neuman JC, Reimer CA, Wang X, Kimple ME, Kudsk KA
(2016) JPEN J Parenter Enteral Nutr 40: 1042-9
MeSH Terms: Animals, Bombesin, Goblet Cells, Hormones, Ectopic, Ileum, Immunity, Innate, Interleukin-13, Interleukin-4, Male, Mice, Mice, Inbred ICR, Mucin-2, Paneth Cells, Parenteral Nutrition, Trefoil Factor-3
Show Abstract · Added August 2, 2016
INTRODUCTION - Parenteral nutrition (PN) increases the risk of infection in critically ill patients and is associated with defects in gastrointestinal innate immunity. Goblet cells produce mucosal defense compounds, including mucin (principally MUC2), trefoil factor 3 (TFF3), and resistin-like molecule β (RELMβ). Bombesin (BBS), a gastrin-releasing peptide analogue, experimentally reverses PN-induced defects in Paneth cell innate immunity. We hypothesized that PN reduces goblet cell product expression and PN+BBS would reverse these PN-induced defects.
METHODS - Two days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 15), PN (n = 13), or PN+BBS (15 µg tid) (n = 12) diets for 5 days. Defined segments of ileum and luminal fluid were analyzed for MUC2, TFF3, and RELMβ by quantitative reverse transcriptase polymerase chain reaction and Western blot. Th2 cytokines interleukin (IL)-4 and IL-13 were measured by enzyme-linked immunosorbent assay.
RESULTS - Compared with chow, PN significantly reduced MUC2 in ileum (P < .01) and luminal fluid (P = .01). BBS supplementation did not improve ileal or luminal MUC2 compared with PN (P > .3). Compared with chow, PN significantly reduced TFF3 in ileum (P < .02) and luminal fluid (P < .01). BBS addition did not improve ileal or luminal TFF3 compared with PN (P > .3). Compared with chow, PN significantly reduced ileal RELMβ (P < .01). BBS supplementation significantly increased ileal RELMβ to levels similar to chow (P < .03 vs PN; P > .6 vs chow). Th2 cytokines were decreased with PN and returned to chow levels with BBS.
CONCLUSION - PN significantly impairs the goblet cell component of innate mucosal immunity. BBS only preserves goblet cell RELMβ during PN but not other goblet cell products measured.
© 2015 American Society for Parenteral and Enteral Nutrition.
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15 MeSH Terms
IL4 receptor α mediates enhanced glucose and glutamine metabolism to support breast cancer growth.
Venmar KT, Kimmel DW, Cliffel DE, Fingleton B
(2015) Biochim Biophys Acta 1853: 1219-28
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Glucose, Glucose Transporter Type 1, Glutamine, Humans, Interleukin-4, Mammary Neoplasms, Animal, Membrane Transport Proteins, Mice, Receptors, Interleukin-4
Show Abstract · Added September 28, 2015
The type II interleukin-4 receptor (IL4R) is expressed in human breast cancer, and in murine models thereof. It is activated by interleukin-4 (IL4), a cytokine produced predominantly by immune cells. Previously, we showed that expression of IL4Rα, a signaling component of IL4R, mediates enhanced metastatic growth through promotion of tumor cell survival and proliferation. In lymphocytes, these processes are supported by increased glucose and glutamine metabolism, and B lymphocyte survival is dependent upon IL4/IL4R-induced glucose metabolism. However, it is unknown whether IL4R-mediated metabolic reprogramming could support tumor growth. Here, we show that IL4Rα expression increases proliferation thus enhancing primary mammary tumor growth. In vitro, IL4-enhanced glucose consumption and lactate production in 4T1 cells was mediated by IL4Rα. Expression of the glucose transporter GLUT1 increased in response to IL4 in vitro, and enhanced GLUT1 expression was associated with the presence of IL4Rα in 4T1 mammary tumors in vivo. Although IL4 treatment did not induce changes in glucose metabolism in MDA-MB-231 human breast cancer cells, it increased expression of the main glutamine transporter, ASCT2, and enhanced glutamine consumption in both MDA-MB-231 and 4T1 cells. Pharmacologic inhibition of glutamine metabolism with compound 968 blocked IL4/IL4Rα-increased cell number in both cell lines. Our results demonstrate that IL4R mediates enhanced glucose and glutamine metabolism in 4T1 cancer cells, and that IL4-induced growth is supported by IL4/IL4R-enhanced glutamine metabolism in both human and murine mammary cancer cells. This highlights IL4Rα as a possible target for effective breast cancer therapy.
Copyright © 2015 Elsevier B.V. All rights reserved.
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14 MeSH Terms
TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.
Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, Polack FP
(2015) J Clin Invest 125: 571-82
MeSH Terms: Animals, Bronchiolitis, Viral, Disease Models, Animal, Environmental Exposure, Female, GATA3 Transcription Factor, Genotype, Humans, Infant, Infant, Newborn, Interferon-gamma, Interleukin-4, Lipopolysaccharides, Male, Mice, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, T-Box Domain Proteins, Th2 Cells, Toll-Like Receptor 4
Show Abstract · Added January 20, 2015
While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
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20 MeSH Terms