Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 34
Filter
Add more filters










Publication year range
1.
EBioMedicine ; 103: 105132, 2024 May.
Article in English | MEDLINE | ID: mdl-38677182

ABSTRACT

BACKGROUND: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. METHODS: To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. FINDINGS: We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. INTERPRETATION: IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19. FUNDING: The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.


Subject(s)
COVID-19 , Cytokine Receptor gp130 , Disease Models, Animal , Interleukin-6 , Mice, Transgenic , SARS-CoV-2 , Signal Transduction , Animals , Interleukin-6/metabolism , COVID-19/metabolism , Humans , Mice , Signal Transduction/drug effects , Cytokine Receptor gp130/metabolism , Cytokine Receptor gp130/antagonists & inhibitors , Recombinant Fusion Proteins/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Lung/pathology , Lung/virology , Lung/metabolism , Endothelial Cells/metabolism , COVID-19 Drug Treatment , Betacoronavirus , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Coronavirus Infections/pathology , Receptors, Interleukin-6/metabolism , Receptors, Interleukin-6/antagonists & inhibitors , Severity of Illness Index
2.
JCI Insight ; 8(24)2023 Dec 22.
Article in English | MEDLINE | ID: mdl-37917179

ABSTRACT

Monocyte-derived macrophages, the major source of pathogenic macrophages in COVID-19, are oppositely instructed by macrophage CSF (M-CSF) or granulocyte macrophage CSF (GM-CSF), which promote the generation of antiinflammatory/immunosuppressive MAFB+ (M-MØ) or proinflammatory macrophages (GM-MØ), respectively. The transcriptional profile of prevailing macrophage subsets in severe COVID-19 led us to hypothesize that MAFB shapes the transcriptome of pulmonary macrophages driving severe COVID-19 pathogenesis. We have now assessed the role of MAFB in the response of monocyte-derived macrophages to SARS-CoV-2 through genetic and pharmacological approaches, and we demonstrate that MAFB regulated the expression of the genes that define pulmonary pathogenic macrophages in severe COVID-19. Indeed, SARS-CoV-2 potentiated the expression of MAFB and MAFB-regulated genes in M-MØ and GM-MØ, where MAFB upregulated the expression of profibrotic and neutrophil-attracting factors. Thus, MAFB determines the transcriptome and functions of the monocyte-derived macrophage subsets that underlie pulmonary pathogenesis in severe COVID-19 and controls the expression of potentially useful biomarkers for COVID-19 severity.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/metabolism , COVID-19/metabolism , Macrophages/metabolism , Macrophages, Alveolar/metabolism , Biomarkers/metabolism , MafB Transcription Factor/genetics , MafB Transcription Factor/metabolism
3.
Aging Cell ; 22(3): e13771, 2023 03.
Article in English | MEDLINE | ID: mdl-36704839

ABSTRACT

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool.


Subject(s)
COVID-19 , Quercetin , Mice , Humans , Animals , Quercetin/pharmacology , Quercetin/therapeutic use , Dasatinib/pharmacology , Dasatinib/therapeutic use , SARS-CoV-2 , Cellular Senescence , Senotherapeutics , Pandemics
4.
Hum Mol Genet ; 31(22): 3789-3806, 2022 11 10.
Article in English | MEDLINE | ID: mdl-35708486

ABSTRACT

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.


Subject(s)
COVID-19 , Genome-Wide Association Study , Female , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , COVID-19/genetics , Sex Characteristics , Genetic Loci , Genetic Predisposition to Disease
5.
Front Immunol ; 13: 891456, 2022.
Article in English | MEDLINE | ID: mdl-35634332

ABSTRACT

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.


Subject(s)
COVID-19 , Interleukin-6 , Receptors, Interleukin-6 , Signal Transduction , COVID-19/diagnosis , COVID-19/immunology , Cytokine Receptor gp130/metabolism , Humans , Interleukin-6/metabolism , Receptors, Interleukin-6/metabolism , Severity of Illness Index
6.
J Innate Immun ; 14(3): 243-256, 2022.
Article in English | MEDLINE | ID: mdl-34670213

ABSTRACT

During inflammatory responses, monocytes are recruited into inflamed tissues, where they become monocyte-derived macrophages and acquire pro-inflammatory and tissue-damaging effects in response to the surrounding environment. In fact, monocyte-derived macrophage subsets are major pathogenic cells in inflammatory pathologies. Strikingly, the transcriptome of pathogenic monocyte-derived macrophage subsets resembles the gene profile of macrophage colony-stimulating factor (M-CSF)-primed monocyte-derived human macrophages (M-MØ). As M-MØ display a characteristic cytokine profile after activation (IL10high TNFlow IL23low IL6low), we sought to determine the transcriptional signature of M-MØ upon exposure to pathogenic stimuli. Activation of M-MØ led to the acquisition of a distinctive transcriptional profile characterized by the induction of a group of genes (Gene set 1) highly expressed by pathogenic monocyte-derived macrophages in COVID-19 and whose presence in tumor-associated macrophages (TAM) correlates with the expression of macrophage-specific markers (CD163, SPI1) and IL10. Indeed, Gene set 1 expression was primarily dependent on ERK/p38 and STAT3 activation, and transcriptional analysis and neutralization experiments revealed that IL-10 is not only required for the expression of a subset of genes within Gene set 1 but also significantly contributes to the idiosyncratic gene signature of activated M-MØ. Our results indicate that activation of M-CSF-dependent monocyte-derived macrophages induces a distinctive gene expression profile, which is partially dependent on IL-10, and identifies a gene set potentially helpful for macrophage-centered therapeutic strategies.


Subject(s)
COVID-19 , Macrophage Colony-Stimulating Factor , Cell Differentiation , Cells, Cultured , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Interleukin-10/genetics , Interleukin-10/metabolism , Macrophage Colony-Stimulating Factor/metabolism , Macrophages/metabolism , Monocytes/metabolism
7.
Nat Rev Gastroenterol Hepatol ; 18(11): 787-803, 2021 11.
Article in English | MEDLINE | ID: mdl-34211157

ABSTRACT

IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.


Subject(s)
Cytokine Receptor gp130/metabolism , Diabetes Mellitus, Type 2/metabolism , Inflammatory Bowel Diseases/metabolism , Interleukin-6/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Obesity/metabolism , Animals , Cytokines/metabolism , Cytokines/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Humans , Immunoglobulin G/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Janus Kinase Inhibitors/therapeutic use , Molecular Targeted Therapy , Non-alcoholic Fatty Liver Disease/drug therapy , Obesity/drug therapy , Recombinant Fusion Proteins/therapeutic use , Signal Transduction
9.
Nutrients ; 12(11)2020 Nov 12.
Article in English | MEDLINE | ID: mdl-33198247

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years. Diet and exercise interventions are the first-line treatment options, with weight loss via a hypocaloric diet being the most important therapeutic target in NAFLD. However, most NAFLD patients are not able to achieve such weight loss. Therefore, the requisite is the investigation of other effective therapeutic approaches. This review summarizes research on understanding complex pathophysiology underlying dietary approaches and exercise interventions with the potential to prevent and treat NAFLD.


Subject(s)
Diet, Reducing , Exercise/physiology , Life Style , Non-alcoholic Fatty Liver Disease/therapy , Humans , Weight Loss
10.
FASEB J ; 34(12): 15875-15887, 2020 12.
Article in English | MEDLINE | ID: mdl-33047392

ABSTRACT

It is becoming clear that several human pathologies are caused by altered metabolic adaptations. During liver development, there are physiological changes, from the predominant utilization of glucose (fetal life) to the use of lipids (postnatal life). Fasting is another physiological stress that elicits well-known metabolic adjustments. We have reported the metabolic properties of cardiotrophin-1 (CT-1), a member of the interleukin-6 family of cytokines. Here, we aimed at analyzing the role of CT-1 in response to these metabolic changes. We used different in vivo models. Furthermore, a differential study was carried out with wild-type and CT-1 null mice in fed (ad libitum) and food-restricted conditions. We demonstrated that Ct-1 is a metabolic gene induced in the liver via PPARα in response to lipids in mice (neonates- and food-restricted adults). We found that Ct-1 mRNA expression in white adipose tissue directly involved PPARα and PPARγ. Finally, the physiological role of CT-1 in fasting is confirmed by the impaired food restriction-induced adipose tissue lipid mobilization in CT-1 null mice. Our findings support a previously unrecognized physiological role of CT-1 in metabolic adaptations, through the regulation of lipid metabolism and contributes to fasting-induced free fatty acid mobilization.


Subject(s)
Adaptation, Physiological/physiology , Fasting/metabolism , Lipid Metabolism/physiology , Solute Carrier Family 22 Member 5/metabolism , 3T3 Cells , Adipose Tissue, White/metabolism , Animals , Cell Line , Cytokines/metabolism , Fatty Acids/metabolism , Glucose/metabolism , Liver , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , PPAR alpha/metabolism , PPAR gamma/metabolism , RNA, Messenger/metabolism
11.
FASEB J ; 33(6): 7578-7587, 2019 06.
Article in English | MEDLINE | ID: mdl-30892966

ABSTRACT

Macrophages play a central role in tissue remodeling, repair, and resolution of inflammation. Macrophage polarization to M1 or M2 activation status may determine the progression or resolution of the inflammatory response. We have previously reported that cardiotrophin-1 (CT-1) displays both cytoprotective and metabolic activities. The role of CT-1 in inflammation remains poorly understood. Here, we employed recombinant CT-1 (rCT-1) and used CT-1-null mice and myeloid-specific CT-1 transgenic mice to investigate whether CT-1 might play a role in the modulation of the inflammatory response. We observed that CT-1 deficiency was associated with enhanced release of inflammatory mediators and with stronger activation of NF-κB in response to LPS, whereas the inflammatory response was attenuated in CT-1 transgenic mice or by administering rCT-1 to wild-type animals prior to LPS challenge. We found that CT-1 promoted IL-6 expression only by nonhematopoietic cells, whereas LPS up-regulated IL-6 expression in both hematopoietic and nonhematopoietic cells. Notably, rCT-1 inhibited LPS-mediated soluble IL-6R induction. Using IL-6-/- mice, we showed that rCT-1 inhibited LPS-induced TNF-α and IFN-γ response in an IL-6-independent manner. Importantly, we demonstrated that CT-1 primes macrophages for IL-4-dependent M2 polarization by inducing IL-4 receptor expression. Mechanistic analyses showed that the signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 axis mediates this effect. Our findings support the notion that CT-1 is a critical regulator of inflammation and suggest that rCT-1 could be a molecule with potential therapeutic application in inflammatory conditions.-Carneros, D., Santamaría, E. M., Larequi, E., Vélez-Ortiz, J. M., Reboredo, M., Mancheño, U., Perugorria, M. J., Navas, P., Romero-Gómez, M., Prieto, J., Hervás-Stubbs, S., Bustos, M. Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.


Subject(s)
Cell Polarity , Cytokines/physiology , Inflammation/prevention & control , Interleukin-4/physiology , Macrophages/cytology , Animals , Interleukin-6/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic
12.
FASEB J ; 31(4): 1639-1649, 2017 04.
Article in English | MEDLINE | ID: mdl-28096235

ABSTRACT

Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo2) was disrupted in aged obese CT-1-deficient (CT-1-/-) mice (12 mo). Although circadian rhythms of Vo2 were conserved in young lean CT-1-/- mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1-/- mice. However, the pattern was altered in CT-1-/- mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.-López-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gómez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escoté, X., Lee, V., Nunez, M. V., Medici, V., Martínez-Ansó, E., Sáinz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J., Martínez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.


Subject(s)
Adipose Tissue/metabolism , CLOCK Proteins/genetics , Circadian Rhythm , Cytokines/metabolism , Obesity/metabolism , Adipose Tissue/physiology , Adolescent , Adult , Animals , CLOCK Proteins/metabolism , Cytokines/blood , Cytokines/genetics , Female , Humans , Male , Mice , Mice, Inbred C57BL , Obesity/blood , Oxygen Consumption
13.
J Cell Physiol ; 232(9): 2469-2477, 2017 Sep.
Article in English | MEDLINE | ID: mdl-27608275

ABSTRACT

Cardiotrophin-1 (CT-1) belongs to the IL-6 family of cytokines. Previous studies of our group revealed that CT-1 is a key regulator of glucose and lipid metabolism. The aim of the present study was to analyze the in vitro and in vivo effects of CT-1 on the production of several adipokines involved in body weight regulation, nutrient metabolism, and inflammation. For this purpose, 3T3-L1 adipocytes were incubated with recombinant protein CT-1 (rCT-1) (1-40 ng/ml) for 1 and 18 h. Moreover, the acute effects of rCT-1 administration (0.2 mg/kg, i.v.) for 30 min and 3 h on adipokines levels were also evaluated in high-fat fed obese mice. In 3T3-L1 adipocytes, rCT-1 treatment downregulated the expression and secretion of leptin, resistin, and visfatin. However, rCT-1 significantly stimulated apelin mRNA and secretion. rCT-1 (18 h) also promoted the activation by phosphorylation of AKT, ERK 1/2, and STAT3. Interestingly, pre-treatment with the PI3K inhibitor LY294002 reversed the stimulatory effects of rCT-1 on apelin expression, suggesting that this pathway could be mediating the effects of rCT-1 on apelin production. In contrast, acute administration of rCT-1 (30 min and 3 h) to diet-induced obese mice downregulated leptin and resistin, without significantly modifying apelin or visfatin mRNA in adipose tissue. Furthermore, CT-1 null mice exhibited altered expression of adipokines in adipose tissue. The present study demonstrates that rCT-1 modulates the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be involved in the metabolic actions of this cytokine. J. Cell. Physiol. 232: 2469-2477, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Adipocytes/metabolism , Adipokines/metabolism , Adipose Tissue/metabolism , Cytokines/metabolism , Obesity/metabolism , 3T3-L1 Cells , Adipokines/genetics , Animals , Apelin , Cytokines/deficiency , Cytokines/genetics , Diet, High-Fat , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Leptin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nicotinamide Phosphoribosyltransferase/metabolism , Obesity/etiology , Obesity/genetics , Obesity/physiopathology , Phosphatidylinositol 3-Kinase/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Resistin/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction
14.
Cytokine Growth Factor Rev ; 26(5): 523-32, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26188636

ABSTRACT

Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines that have pleiotropic functions on different tissues and cell types. Although many effects of CT-1 have been described on the heart, there is an extensive research showing important protective effects in other organs such as liver, kidney or nervous system. Recently, several studies have pointed out that CT-1 might also play a key role in the regulation of body weight and intermediate metabolism. This paper will review many aspects of CT-1 physiological role in several organs and discuss data for consideration in therapeutic approaches.


Subject(s)
Cytokines/metabolism , Kidney/metabolism , Liver/metabolism , Myocardium/metabolism , Nervous System/metabolism , Animals , Body Weight , Cytokines/genetics , Humans
15.
J Lipid Res ; 55(12): 2634-43, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25351614

ABSTRACT

Cardiotrophin-1 (CT-1) is a cytokine with antiobesity properties and with a role in lipid metabolism regulation and adipose tissue function. The aim of this study was to analyze the molecular mechanisms involved in the lipolytic actions of CT-1 in adipocytes. Recombinant CT-1 (rCT-1) effects on the main proteins and signaling pathways involved in the regulation of lipolysis were evaluated in 3T3-L1 adipocytes and in mice. rCT-1 treatment stimulated basal glycerol release in a concentration- and time-dependent manner in 3T3-L1 adipocytes. rCT-1 (20 ng/ml for 24 h) raised cAMP levels, and in parallel increased protein kinase (PK)A-mediated phosphorylation of perilipin and hormone sensitive lipase (HSL) at Ser660. siRNA knock-down of HSL or PKA, as well as pretreatment with the PKA inhibitor H89, blunted the CT-1-induced lipolysis, suggesting that the lipolytic action of CT-1 in adipocytes is mainly mediated by activation of HSL through the PKA pathway. In ob/ob mice, acute rCT-1 treatment also promoted PKA-mediated phosphorylation of perilipin and HSL at Ser660 and Ser563, and increased adipose triglyceride lipase (desnutrin) content in adipose tissue. These results showed that the ability of CT-1 to regulate the activity of the main lipases underlies the lipolytic action of this cytokine in vitro and in vivo, and could contribute to CT-1 antiobesity effects.


Subject(s)
Adipocytes, White/metabolism , Carrier Proteins/metabolism , Cytokines/metabolism , Lipase/metabolism , Lipolysis , Phosphoproteins/metabolism , Sterol Esterase/metabolism , Up-Regulation , 3T3-L1 Cells , Adipocytes, White/drug effects , Adipocytes, White/enzymology , Animals , Carrier Proteins/biosynthesis , Cell Cycle Proteins/agonists , Cell Cycle Proteins/metabolism , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP-Dependent Protein Kinases/chemistry , Cyclic AMP-Dependent Protein Kinases/metabolism , Cytokines/genetics , Enzyme Activation/drug effects , Enzyme Activators/pharmacology , Gene Silencing , Lipase/antagonists & inhibitors , Lipase/chemistry , Lipolysis/drug effects , Male , Mice , Mice, Mutant Strains , Perilipin-1 , Phosphoproteins/biosynthesis , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Processing, Post-Translational , Recombinant Proteins/metabolism , Signal Transduction/drug effects , Sterol Esterase/antagonists & inhibitors , Sterol Esterase/chemistry , Sterol Esterase/genetics , Up-Regulation/drug effects
16.
J Hepatol ; 60(5): 1017-25, 2014 May.
Article in English | MEDLINE | ID: mdl-24362075

ABSTRACT

BACKGROUND & AIMS: Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD). METHODS: rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice. Livers were analyzed for lipid composition and expression of genes involved in fat metabolism. We studied the effects of rCT-1 on lipogenesis and fatty acid (FA) oxidation in liver cells and the ability of dominant negative inhibitor of AMP-activated protein kinase (AMPK) to block these effects. RESULTS: CT-1 was found to be upregulated in human and murine steatotic livers. In two NAFLD mouse models, treatment with rCT-1 for 10days induced a marked decrease in liver triglyceride content with augmented proportion of poly-unsaturated FA and reduction of monounsaturated species. These changes were accompanied by attenuation of inflammation and improved insulin signaling. Chronic administration of rCT-1 caused downregulation of lipogenic genes and genes involved in FA import to hepatocytes together with amelioration of ER stress, elevation of NAD(+)/NADH ratio, phosphorylation of LKB1 and AMPK, increased expression and activity of sirtuin1 (SIRT1) and upregulation of genes mediating FA oxidation. rCT-1 potently inhibited de novo lipogenesis and stimulated FA oxidation in liver cells both in vitro and in vivo. In vitro studies showed that these effects are mediated by activated AMPK. CONCLUSIONS: rCT-1 resolves hepatic steatosis in obese mice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Cytokines/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Cytokines/genetics , Cytokines/therapeutic use , Diet, High-Fat/adverse effects , Disease Models, Animal , Enzyme Activation , Fatty Acids/metabolism , Hepatocytes/metabolism , Humans , Insulin Resistance , Lipid Metabolism , Lipogenesis , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Obese , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recombinant Proteins/therapeutic use , Sirtuin 1/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Transcription Factors/metabolism , Up-Regulation
17.
Metabolism ; 62(10): 1429-36, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23856329

ABSTRACT

OBJECTIVE: Cardiotrophin-1 (CT-1) shares some similarities with other cytokines, and participates in the control of energy metabolism. Higher circulating levels are observed in obese humans, but little information is gathered in weight loss (WL) programs. Therefore, we aimed to investigate the association of serum CT-1 levels with metabolic variables and the risk of developing metabolic syndrome (MetS) after a WL program in overweight/obese children. SUBJECTS AND METHODS: Forty-four overweight/obese children (mean age 11.5 y; 50% males) undergoing a 10-week WL program were enrolled. Subjects were dichotomized at the median of Body Mass Index-Standard Deviation Score (BMI-SDS) change, as high and low responders after intervention. RESULTS: CT-1 levels were significantly reduced (-48 fmol/mL, p=0.043) in the high responder group after the WL program. They had significantly lower body weight (-3.7 kg, p<0.001), body fat mass (-8%, p<0.001), BMI-SDS (-0.78, p<0.001) and waist circumference (-5.4 cm, p<0.001), and a significant improvement in lipid and glucose profiles (p<0.05). Interestingly, decreased CT-1 levels significantly predicted changes in total cholesterol (41%) and LDL-cholesterol (28%). Moreover, in our participants the lower the CT-1 levels, the higher the reduction in MetS risk components, after the 10-week intervention, (p-ANCOVA=0.040, p-trend=0.024). CONCLUSION: We showed, for the first time, a reduction in serum CT-1 levels after a WL program and this decrease in CT-1 was strongly associated with a reduction in cholesterol levels and in MetS risk factors in overweight/obese children. Our findings may suggest that CT-1 could be an indirect marker for the diagnosis of MetS in this population.


Subject(s)
Cytokines/metabolism , Metabolic Syndrome/metabolism , Metabolic Syndrome/prevention & control , Obesity/metabolism , Overweight/metabolism , Adipose Tissue/metabolism , Blood Glucose/metabolism , Body Mass Index , Child , Cholesterol/metabolism , Cholesterol, LDL/metabolism , Female , Humans , Male , Risk , Waist Circumference/physiology , Weight Loss/physiology , Weight Reduction Programs/methods
18.
J Immunol ; 190(5): 2301-10, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23355731

ABSTRACT

Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization-associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7), whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.


Subject(s)
Biomarkers/metabolism , Cell Differentiation/drug effects , Macrophages/drug effects , Receptor, Serotonin, 5-HT2B/immunology , Receptors, Serotonin/immunology , Serotonin/pharmacology , Animals , Cell Lineage , Cells, Cultured , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Genes, Reporter , Humans , Inflammation/chemically induced , Inflammation/immunology , Inflammation/metabolism , Interleukin-10/biosynthesis , Interleukin-10/immunology , Kupffer Cells/cytology , Kupffer Cells/drug effects , Kupffer Cells/immunology , Lipopolysaccharides , Luciferases , Macrophages/cytology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Receptor, Serotonin, 5-HT2B/genetics , Receptors, Serotonin/genetics , Serotonin/immunology , Signal Transduction/drug effects
19.
Oncoimmunology ; 1(9): 1527-1536, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23264899

ABSTRACT

Cardiotrophin-1 (CT-1/CTF1) is a member of the interleukin-6 (IL-6) family of cytokines that stimulates STAT-3 phosphorylation in cells bearing the cognate receptor. We report that Ctf1(-/-) mice (hereby referred to as CT-1(-/-) mice) are resistant to the hepatic engraftment of MC38 colon carcinoma cells, while these cells engraft normally in the mouse subcutaneous tissue. Tumor intake in the liver could be enhanced by the systemic delivery of a recombinant adenovirus encoding CT-1, which also partly rescued the resistance of CT-1(-/-) mice to the hepatic engraftment of MC38 cells. Moreover, systemic treatment of wild-type (WT) mice with a novel antibody-neutralizing mouse CT-1 also reduced engraftment of this model. Conversely, experiments with Panc02 pancreatic cancer and B16-OVA melanoma cells in CT-1(-/-) mice revealed rates of hepatic engraftment similar to those observed in WT mice. The mechanism whereby CT-1 renders the liver permissive for MC38 metastasis involves T lymphocytes and natural killer (NK) cells, as shown by selective depletion experiments and in genetically deficient mice. However, no obvious changes in the number or cell killing capacity of liver lymphocytes in CT-1(-/-) animals could be substantiated. These findings demonstrate that the seed and soil concept to understand metastasis can be locally influenced by cytokines as well as by the cellular immune system.

20.
J Nutr Biochem ; 23(3): 218-27, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21497077

ABSTRACT

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid with beneficial effects in obesity and insulin resistance. High levels of proinflammatory cytokine tumour necrosis factor-α (TNF-α) in obesity promote lipolysis in adipocytes, leading to the development of insulin resistance. Thus, the aims of the present study were to analyze the potential antilipolytic properties of EPA on cytokine-induced lipolysis and to investigate the possible mechanisms involved. The EPA effects on basal and TNF-α-induced lipolysis were determined in both primary rat and 3T3-L1 adipocytes. Treatment of primary rat adipocytes with EPA (100 and 200 µM) significantly decreased basal glycerol release (P<.01) and prevented cytokine-induced lipolysis in a dose-dependent manner (P<.001). Moreover, EPA decreased TNF-α-induced activation of nuclear factor-κB and extracellular-related kinase 1/2 phosphorylation. In addition, the antilipolytic action of EPA was stimulated by the AMP-kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside and blocked by the AMPK-inhibitor compound C. Moreover, we found that EPA stimulated hormone-sensitive lipase (HSL) phosphorylation on serine-565, which further supports the involvement of AMPK in EPA's antilipolytic actions. Eicosapentaenoic acid treatment (24 h), alone and in the presence of TNF-α, also decreased adipose triglyceride lipase (ATGL) protein content in cultured adipocytes. However, oral supplementation with EPA for 35 days was able to partially reverse the down-regulation of HSL and ATGL messenger RNA observed in retroperitoneal adipose tissue of high-fat-diet-fed rats. These findings suggest that EPA inhibits proinflammatory cytokine-induced lipolysis in adipocytes. This effect might contribute to explain the insulin-sensitizing properties of EPA.


Subject(s)
Adipocytes/drug effects , Eicosapentaenoic Acid/pharmacology , Lipolysis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , 3T3-L1 Cells , Adenylate Kinase/metabolism , Adipocytes/cytology , Adipocytes/metabolism , Administration, Oral , Animals , Diet, High-Fat , Down-Regulation , Insulin/metabolism , Intra-Abdominal Fat/metabolism , Lipase/metabolism , Male , Mice , NF-kappa B/metabolism , Phosphorylation , Rats , Rats, Wistar , Sterol Esterase/genetics , Sterol Esterase/metabolism , Tumor Necrosis Factor-alpha/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...