bims-stacyt 2024-10-20 papers

Cells. 2024 Sep 24. pii: 1603. [Epub ahead of print]13(19):

Altered Cytokine Secretory Fingerprint of the Adipocytes Derived from Stem Cells of Morbidly Obese Patients-A Preliminary Study.

Bartłomiej Łukaszuk, Elżbieta Supruniuk, Adrian Chabowski, Agnieszka Mikłosz.

Context: Adipose-derived mesenchymal stem cells (ADMSCs) are progenitor cells that shape the tissue's biological properties. Objective: To examine the adipocytes differentiated from the ADMSCs of lean and obese individuals with/without a metabolic syndrome (MetSx) cytokine secretory profile, as to date, little is known on this topic. Methods: Interleukin, chemokine and growth factor levels in the culture medium were determined using the Human Cytokine kit. Results: We observed a characteristic secretory fingerprint displayed by the cells from the MetSx group and identified a set of putative markers (IL-1β, IL-6, IL-7, IL-10, IL-12, IL-13, VEGF, FGF, GM-CSF, TNF-α, IFN-γ) of the condition. Surprisingly, the concentrations of most of the molecules (except for IL-6, IFN-γ, IP-10, VEGF) decreased when compared with the cells from the lean group. We postulate that the difference stemmed from the fact that in vivo cytokines were mostly secreted by the activated monocytes/macrophages and not adipocytes per se. This may also suggest that the aforementioned upregulated cytokines (IL-6, IFN-γ, IP-10, VEGF) might have been the ones that attracted monocytes and triggered the vicious cycle of tissue inflammation. Conclusions: Our study indicated that the adipocytes newly derived from the ADMSCs of obese patients with metabolic syndrome displayed a secretory fingerprint that may be characteristic to the early stages of the condition.

Keywords: ADMSCs; IL-6; adipose tissue; cytokines; metabolic syndrome; stem cells

DOI: https://doi.org/10.3390/cells13191603

Sci Rep. 2024 10 14. 14(1): 23993

Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction.

Kento Takeuchi, Kanji Yamaguchi, Yusuke Takahashi, Kota Yano, Shinya Okishio, Hiroshi Ishiba, Nozomi Tochiki, Seita Kataoka, Hideki Fujii, Naoto Iwai, Yuya Seko, Atsushi Umemura, Michihisa Moriguchi, Takeshi Okanoue, Yoshito Itoh.

GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.

Keywords: ER stress; FGF21; GDF15; Hepatokine; MASLD; NAFLD

DOI: https://doi.org/10.1038/s41598-024-75107-8

Contemp Oncol (Pozn). 2024 ;28(2): 114-120

Evaluation of selected circulating cytokines from the IL-6 family - interleukin 6, oncostatin M, and cardiotrophin-1 - in gastro-entero-pancreatic and bronchial neuroendocrine tumours.

Janusz Strzelczyk, Ksenia Janas, Joanna Katarzyna Strzelczyk, Elżbieta Chełmecka, Dariusz Kajdaniuk, Beata Kos-Kudła.

Introduction: The incidence of neuroendocrine tumours (NETs) increased over the last years. Most of them are non-functioning, and the course of the disease is asymptomatic for a long time. This results in late diagnosis at an advanced stage. The aim of our study was the evaluation of selected circulating cytokines of interleukin-6 family - interleukin 6 (IL-6), oncostatin M (OSM), and cardiotrophin-1 (CT1) - in NETs.
Material and methods: The study group comprised 80 patients (56%) in several subgroups, including gastroenteropancreatic (GEPNETs, n = 64, 80%) and bronchopulmonary neuroendocrine tumours (BPNETs, n = 16; 20%). Serum IL-6, OSM, and CT1 concentrations were tested using ELISA.
Results: The median concentration of IL-6 was 41.5 pg/ml in the study group and 32.6 pg/ml in the control group, and the difference was statistically significant (p < 0.001). The concentration of OSM was significantly lower in the study group than in the control group (p < 0.001), at 105.6 pg/ml and 115.5 pg/ml, respectively. There was a significant difference (p < 0.01) in concentration of CT1 in the study group (222.0 pg/ml) and controls (267.2 pg/ml). Our investigation into selected IL-6 family cytokines revealed differential modulation of signal transduction pathways.
Conclusions: These findings suggest that despite utilising a common signalling transducer, individual IL-6 family cytokines exert distinct biological effects on neuroendocrine tumour development. Notably, IL-6 appears to promote tumourigenesis, while OSM and CT1 exhibit inhibitory effects on gastro-entero-pancreatic and bronchial neuroendocrine tumour development. Further studies are necessary to validate the diagnostic utility of IL-6 family cytokines in NETs.

Keywords: BPNET; CT1; GEPNET; IL-6; IL-6 family; OSM; biomarker; cytokines; neuroendocrine tumours

DOI: https://doi.org/10.5114/wo.2024.142584

EMBO Rep. 2024 Oct 18.

Glycogenesis and glyconeogenesis from glutamine, lactate and glycerol support human macrophage functions.

Najia Jeroundi, Charlotte Roy, Laetitia Basset, Pascale Pignon, Laurence Preisser, Simon Blanchard, Cinzia Bocca, Cyril Abadie, Julie Lalande, Naïg Gueguen, Guillaume Mabilleau, Guy Lenaers, Aurélie Moreau, Marie-Christine Copin, Guillaume Tcherkez, Yves Delneste, Dominique Couez, Pascale Jeannin.

Macrophages fight infection and ensure tissue repair, often operating at nutrient-poor wound sites. We investigated the ability of human macrophages to metabolize glycogen. We observed that the cytokines GM-CSF and M-CSF plus IL-4 induced glycogenesis and the accumulation of glycogen by monocyte-derived macrophages. Glyconeogenesis occurs in cells cultured in the presence of the inflammatory cytokines GM-CSF and IFNγ (M1 cells), via phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose-1,6-bisphosphatase 1 (FBP1). Enzyme inhibition with drugs or gene silencing techniques and 13C-tracing demonstrate that glutamine (metabolized by the TCA cycle), lactic acid, and glycerol were substrates of glyconeogenesis only in M1 cells. Tumor-associated macrophages (TAMs) also store glycogen and can perform glyconeogenesis. Finally, macrophage glycogenolysis and the pentose phosphate pathway (PPP) support cytokine secretion and phagocytosis regardless of the availability of extracellular glucose. Thus, glycogen metabolism supports the functions of human M1 and M2 cells, with inflammatory M1 cells displaying a possible dependence on glyconeogenesis.

Keywords: Cytokine secretion; Glycogenolysis; Glyconeogenesis; Macrophages; Phagocytosis

DOI: https://doi.org/10.1038/s44319-024-00278-4

Int J Mol Sci. 2024 Sep 26. pii: 10384. [Epub ahead of print]25(19):

Physiologically Achievable Concentration of 2-Deoxy-D-Glucose Stimulates IFN-γ Secretion in Activated T Cells In Vitro.

Jernej Repas, Tjaša Frlic, Tadeja Snedec, Andreja Nataša Kopitar, Harald Sourij, Andrej Janež, Mojca Pavlin.

2-deoxy-D-glucose (2DG) is a glycolysis and protein N-glycosylation inhibitor with promising anti-tumor and immunomodulatory effects. However, 2DG can also suppress T cell function, including IFN-γ secretion. Few human T cell studies have studied low-dose 2DG, which can increase IFN-γ in a Jurkat clone. We therefore investigated 2DG's effect on IFN-γ in activated human T cells from PBMCs, with 2DG treatment commenced either concurrently with activation or 48 h after activation. Concurrent 2DG treatment decreased IFN-γ secretion in a dose-dependent manner. However, 2DG treatment of pre-activated T cells had a hormetic effect on IFN-γ, with 0.15-0.6 mM 2DG (achievable in vivo) increasing and >2.4 mM 2DG reducing its secretion. In contrast, IL-2 levels declined monotonously with increasing 2DG concentration. Lower 2DG concentrations reduced PD-1 and increased CD69 expression regardless of treatment timing. The absence of increased T-bet or Eomes expression or IFNG transcription suggests another downstream mechanism. 2DG dose-dependently induced the unfolded protein response, suggesting a possible role in increased IFN-γ secretion, possibly by increasing the ER folding capacity for IFN-γ via increased chaperone expression. Overall, low-dose, short-term 2DG exposure could potentially improve the T cell anti-tumor response.

Keywords: 2-deoxy-D-glucose; CAR T; ER stress; T cells; interferon gamma; mitochondria; protein N-glycosylation

DOI: https://doi.org/10.3390/ijms251910384