Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation.
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ABSTRACT:
SUBMITTER: Breen DM
PROVIDER: S-EPMC8215224 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Analysis of normal human tracheobronchial epithelial cells treated with or without recombinant human GDF15 for two hours. Results provide insights of the genome-wide transcriptional regulation by Smad1 associated with GDF15 in human airway epithelium.
2017-10-08 | GSE100625 | GEO
Project description:Growth differentiation factor-15 (GDF-15) is a member of the TGF-? cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Elevations in GDF-15 may identify a novel pathway involved in loss of kidney function among patients with CKD. Among participants in the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS), we tested whether kidney tissue expression of GDF15 mRNA correlates with circulating levels of GDF-15 and whether elevations in circulating GDF-15 are associated with decline in kidney function. In matching samples of 24 patients with CKD from the C-PROBE study, circulating GDF-15 levels significantly correlated with intrarenal GDF15 transcript levels (r=0.54, P=0.01). Among the 224 C-PROBE and 297 SKS participants, 72 (32.1%) and 94 (32.0%) patients, respectively, reached a composite end point of 30% decline in eGFR or progression to ESRD over a median of 1.8 and 2.0 years of follow up, respectively. In multivariable models, after adjusting for potential confounders, every doubling of GDF-15 level associated with a 72% higher (95% confidence interval, 1.21 to 4.45; P=0.003) and 65% higher (95% confidence interval, 1.08 to 2.50; P=0.02) risk of progression of kidney disease in C-PROBE and SKS participants, respectively. These results show that circulating GDF-15 levels strongly correlated with intrarenal expression of GDF15 and significantly associated with increased risk of CKD progression in two independent cohorts. Circulating GDF-15 may be a marker for intrarenal GDF15-related signaling pathways associated with CKD and CKD progression.
| S-EPMC5491285 | biostudies-literature
Project description:Growth and differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. GDF15 has been linked with several metabolic syndrome pathologies such as obesity and cardiovascular diseases. GDF15 is considered to be a metabolic regulator, although its precise mechanisms of action remain to be determined. Glial cell-derived neurotrophic factor family receptor alpha-like (GRAL), located in the hindbrain, has been identified as the receptor for GDF15 and signals through the coreceptor receptor tyrosine kinase (RET). Administration of GDF15 analogues in preclinical studies using various animal models has consistently been shown to induce weight loss through a reduction in food intake. GDF15, therefore, represents an attractive target to combat the current global obesity epidemic. In this article, we review current knowledge on GDF15 and its involvement in metabolic syndrome.
| S-EPMC10148061 | biostudies-literature
Project description:Purpose of reviewGrowth differentiation factor 15 (GDF15) was identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. This review addresses the regulation, expression and potential functions of GDF15 in the context of erythroid biology.Recent findingsGDF15 expression during late erythroid differentiation was discovered as part of an erythroblast transcriptome project. As GDF15 expression is associated with cellular stress or apoptosis, further investigation of the cytokine was focused upon its involvement in ineffective erythropoiesis. Remarkably high serum levels were detected in patients with thalassemia syndromes, congenital dyserythropoiesis and some acquired sideroblastic anemias. High-level GDF15 expression is not a feature of normal erythropoiesis, or erythroid recovery after bone-marrow transplantation. As GDF15 is a transforming growth factor-beta superfamily member, it was investigated as an effector of ineffective erythropoiesis that suppresses hepcidin expression despite iron overloading.SummaryIn contrast to the low levels of GDF15 expressed during normal erythropoiesis, ineffective erythropoiesis causes high-level expression of GDF15. In patients with thalassemia and related anemias, GDF15 expression may contribute to iron overloading or other features of the disease phenotype.
| S-EPMC2884377 | biostudies-literature
Project description:Human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year round, but the mechanisms have not been well elucidated. Recent clinical studies suggest that high levels of growth differentiation factor 15 (GDF15) protein in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. Therefore, in the current study, we investigated whether GDF15 promotes HRV infection and virus-induced lung inflammation. We first examined the role of GDF15 in regulating host defense and HRV-induced inflammation using human GDF15 transgenic mice and cultured human GDF15 transgenic mouse tracheal epithelial cells. Next, we determined the effect of GDF15 on viral replication, antiviral responses, and inflammation in human airway epithelial cells with GDF15 knockdown and HRV infection. Finally, we explored the signaling pathways involved in airway epithelial responses to HRV infection in the context of GDF15. Human GDF15 protein overexpression in mice led to exaggerated inflammatory responses to HRV, increased infectious particle release, and decreased IFN-λ2/3 (IL-28A/B) mRNA expression in the lung. Moreover, GDF15 facilitated HRV replication and inflammation via inhibiting IFN-λ1/IL-29 protein production in human airway epithelial cells. Lastly, Smad1 cooperated with interferon regulatory factor 7 (IRF7) to regulate airway epithelial responses to HRV infection partly via GDF15 signaling. Our results reveal a novel function of GDF15 in promoting lung HRV infection and virus-induced inflammation, which may be a new mechanism for the increased susceptibility and severity of respiratory viral (i.e., HRV) infection in cigarette smoke-exposed airways with GDF15 overproduction.
| S-EPMC6048458 | biostudies-literature
Project description:BACKGROUND:Despite the growing body of evidence on growth differentiation factor 15 (GDF-15) reference values for patients with existing cardiovascular disease, limited investigation has been dedicated to characterizing the distribution and prognostic impact of GDF-15 in predominantly healthy populations. Furthermore, current cutoff values for GDF-15 fail to account for the well-documented age-dependence of circulating GDF-15. METHODS:From 810 community-dwelling older adults, we selected a group of apparently healthy participants (n?=?268). From this sample, circulating GDF-15 was modeled using the generalized additive models for location scale and shape (GAMLSS) to develop age-dependent centile values. Unadjusted and adjusted Cox proportional hazards models were used to assess the association between the derived GDF-15 reference values (expressed as centiles) and all-cause mortality. RESULTS:Smoothed centile curves showed increasing GDF-15 with age in the apparently healthy participants. An approximately three-fold difference was observed between the 95th and 5th GDF-15 centiles across ages. In a median 8.0 years of follow-up, 97 all-cause deaths were observed in 806 participants with eligible values. In unadjusted Cox regression analyses, the hazard ratio (95% CI) for all-cause mortality per 25-unit increase in GDF-15 centile was 1.80 (1.48-2.20) and dichotomized at the 95th centile, ?95th versus <95th, was 3.04 (1.99-4.65). Age-dependent GDF-15 centiles remained a significant predictor of all-cause mortality in all subsequent adjusted models. CONCLUSIONS:Age-dependent GDF-15 centile values developed from a population of apparently healthy older adults are independently predictive of all-cause mortality. Therefore, GDF-15 reference values could be a useful tool for risk-stratification in a clinical setting. ClinicalTrials.gov Identifier: NCT01452178.
| S-EPMC6055745 | biostudies-literature
Project description:Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.
| S-EPMC7248355 | biostudies-literature
Project description:BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10-8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR-Egger, leave-one-out analysis, and Cochran's Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04-1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.
| S-EPMC8414585 | biostudies-literature
Project description:Growth Differentiation Factor 15 (GDF-15) is a cytokine produced in response to tissue injury and inflammatory states that may capture distinct pathways between the risk factors aggregated within metabolic syndrome (MS) and the development of diabetes and cardiovascular disease. This work aims to study the association of MS and its components with GDF-15 among older adults, examining the roles of body fat distribution, glucose metabolism, and inflammation. Data were taken from the Seniors-ENRICA-2 study in Spain, which included 1938 non-institutionalized individuals aged ≥65 years free of diabetes and cardiovascular disease. MS was defined as the presence of ≥3 of the following components: high waist circumference, elevated fasting blood glucose levels, raised blood pressure, increased triglyceride levels, and low serum high-density lipoprotein (HDL) cholesterol. Statistical analyses were performed with linear regression models and adjusted for potential sociodemographic and lifestyle confounders. MS was associated with higher GDF-15 levels (fully adjusted mean increase [95% confidence interval] = 9.34% [5.16,13.7]). The MS components showing the strongest associations were high waist circumference (6.74% [2.97,10.6]), elevated glucose levels (4.91% [0.77,9.23]), and low HDL-cholesterol (8.13% [3.51,13.0]). High waist-to-hip ratio (7.07% [2.63,11.7]), urine albumin (12.1% [2.57,22.5]), and C-reactive protein (10.4% [3.89,17.3]) were also associated with increased GDF-15. In conclusion, MS was associated with higher GDF-15 levels in older adults. Abdominal obesity, hyperglycemia -possibly linked to microvascular disease, as inferred from elevated urine albumin-, low HDL-cholesterol, and inflammation were the main drivers of this association.
| S-EPMC9135918 | biostudies-literature
Project description:BACKGROUND:Growth differentiation factor 15 (GDF-15), a stress responsive cytokine, belongs to transforming growth factor ? cytokine superfamily. Some evidence support that it's involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and hemostasis. However, it's still controversial whether GDF-15 directly contributes to the morbidity and mortality of patients suffered with cardiovascular disease (CVD). Besides prospective cohort study and randomized controlled trial, Mendelian randomization (MR) is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable to determine the causal relationships between exposures and health outcomes. Herein, we introduced a two-sample MR approach to evaluate the causal relationships of circulating GDF-15 levels with major CVDs incidence. METHODS:Genetic instruments and summary statistics for two-sample MR analysis were obtained from 5 independent large genome-wide association studies (GWAS) to investigate the causal correlation between circulating GDF-15 levels and 9 CVDs, respectively. Conventional inverse variance weighted method was adopted to evaluate the causality of GDF-15 with different outcomes; weighted median and MR egger were used for sensitivity analyses. RESULTS:Among 9 SNPs identified from 5 GWASs in 2.6 million individuals, 5 SNPs (rs1227731, rs3195944, rs17725099, rs888663, rs749451) coming from chromosome 19 and containing the PGPEP1 and GDF-15 genes were employed. Based on the instruments, circulating GDF-15 levels significantly linked to the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction. However, no significant causal association was observed for circulating GDF-15 levels with the incidence of any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. CONCLUSIONS:The MR study provides with genetic evidence for the causal relationship of circulating GDF-15 levels with the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction, but not any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. It indicates that GDF-15 might be a promising biomarker or potential therapeutic target for some CVDs.
| S-EPMC7594331 | biostudies-literature