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Cell Communication and Signaling : CCS Feb 2024R140Q mutation in isocitrate dehydrogenase 2 (IDH2) promotes leukemogenesis. Targeting IDH2/R140Q yields encouraging therapeutic effects in the clinical setting....
BACKGROUND
R140Q mutation in isocitrate dehydrogenase 2 (IDH2) promotes leukemogenesis. Targeting IDH2/R140Q yields encouraging therapeutic effects in the clinical setting. However, therapeutic resistance occurs in 12% of IDH2/R140Q inhibitor treated patients. The IDH2/R140Q mutant converted TF-1 cells to proliferate in a cytokine-independent manner. This study investigated the signaling pathways involved in TF-1(R140Q) cell proliferation conversion as alternative therapeutic strategies to improve outcomes in patients with acute myeloid leukemia (AML) harboring IDH2/R140Q.
METHODS
The effects of IDH2/R140Q mutation on TF-1 cell survival induced by GM-CSF withdrawal were evaluated using flow cytometry assay. The expression levels of apoptosis-related proteins, total or phosphorylated STAT3/5, ERK, and AKT in wild-type TF-1(WT) or TF-1(R140Q) cells under different conditions were evaluated using western blot analysis. Cell viability was tested using MTT assay. The mRNA expression levels of GM-CSF, IL-3, IL-6, G-CSF, leukemia inhibitory factor (LIF), oncostatin M (OSM), and IL-11 in TF-1(WT) and TF-1(R140Q) cells were quantified via RT-PCR. The secretion levels of GM-CSF, OSM, and LIF were determined using ELISA.
RESULTS
Our results showed that STAT3 and STAT5 exhibited aberrant constitutive phosphorylation in TF-1(R140Q) cells compared with TF-1(WT) cells. Inhibition of STAT3/5 phosphorylation suppressed the cytokine-independent proliferation of TF-1(R140Q) cells. Moreover, the autocrine GM-CSF, LIF and OSM levels increased, which is consistent with constitutive STAT5/3 activation in TF-1(R140Q) cells, as compared with TF-1(WT) cells.
CONCLUSIONS
The autocrine cytokines, including GM-CSF, LIF, and OSM, contribute to constitutive STAT3/5 activation in TF-1(R140Q) cells, thereby modulating IDH2/R140Q-mediated malignant proliferation in TF-1 cells. Targeting STAT3/5 phosphorylation may be a novel strategy for the treatment of AML in patients harboring the IDH2/R140Q mutation. Video Abstract.
Topics: Humans; Granulocyte-Macrophage Colony-Stimulating Factor; STAT5 Transcription Factor; Phosphorylation; Leukemia, Myeloid, Acute; Mutation; Cell Proliferation; STAT3 Transcription Factor
PubMed: 38347540
DOI: 10.1186/s12964-023-01367-y -
Kidney International Reports Feb 2024Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly...
INTRODUCTION
Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly due to the removal of tonsillar cytokine-activated cells producing Gd-IgA1. To test this hypothesis, we used immortalized IgA1-producing cell lines derived from tonsils of patients with IgAN or obstructive sleep apnea (OSA) and assessed the effect of leukemia inhibitory factor (LIF) or oncostatin M (OSM) on Gd-IgA1 production.
METHODS
Gd-IgA1 production was measured by lectin enzyme-linked immunosorbent assay; JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates; and validated by using small interfering RNA (siRNA) knock-down and small-molecule inhibitors.
RESULTS
IgAN-derived cells produced more Gd-IgA1 than the cells from patients with OSA, and exhibited elevated Gd-IgA1 production in response to LIF, but not OSM. This effect was associated with dysregulated STAT1 phosphorylation, as confirmed by STAT1 siRNA knock-down. JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with OSA. Based on modeling LIF-LIFR-gp130-JAK2 receptor complex, we postulate that LIF binding to LIFR may sequester gp130 and/or JAK2 from other pathways; and when combined with JAK2 inhibition, enables full blockade of the aberrant -glycosylation pathways in IgAN.
CONCLUSION
In summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN.
PubMed: 38344714
DOI: 10.1016/j.ekir.2023.11.003 -
Cells Jan 2024Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and...
Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and maintaining embryo immunotolerance and protection. In contrast, the unbalanced activity of pro-inflammatory factors such as interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at the maternal-fetal interface have detrimental effects on trophoblast function and differentiation. This study demonstrates how the IL-6 cytokine family member oncostatin M (OSM) and STAT3 activation regulate trophoblast fusion and endocrine function in response to pro-inflammatory stress induced by IFNγ and GM-CSF. Using human cytotrophoblast-like BeWo (CT/BW) cells, differentiated in villous syncytiotrophoblast (VST/BW) cells, we show that beta-human chorionic gonadotrophin (βhCG) production and cell fusion process are affected in response to IFNγ or GM-CSF. However, those effects are abrogated with OSM by modulating the activation of IFNγ-STAT1 and GM-CSF-STAT5 signaling pathways. OSM stimulation enhances the expression of STAT3, the phosphorylation of STAT3 and SMAD2, and the induction of negative regulators of inflammation (e.g., IL-10 and TGFβ1) and cytokine signaling (e.g., SOCS1 and SOCS3). Using STAT3-deficient VST/BW cells, we show that STAT3 expression is required for OSM to regulate the effects of IFNγ in βhCG and E-cadherin expression. In contrast, OSM retains its modulatory effect on GM-CSF-STAT5 pathway activation even in STAT3-deficient VST/BW cells, suggesting that OSM uses STAT3-dependent and -independent mechanisms to modulate the activation of pro-inflammatory pathways IFNγ-STAT1 and GM-CSF-STAT5. Moreover, STAT3 deficiency in VST/BW cells leads to the production of both a large amount of βhCG and an enhanced expression of activated STAT5 induced by GM-CSF, independently of OSM, suggesting a key role for STAT3 in βhCG production and trophoblast differentiation through STAT5 modulation. In conclusion, our study describes for the first time the critical role played by OSM and STAT3 signaling pathways to preserve and regulate trophoblast biological functions during inflammatory stress.
Topics: Pregnancy; Female; Humans; Granulocyte-Macrophage Colony-Stimulating Factor; Interferon-gamma; Oncostatin M; STAT5 Transcription Factor; Interleukin-6; Signal Transduction; Trophoblasts; STAT3 Transcription Factor
PubMed: 38334621
DOI: 10.3390/cells13030229 -
Inflammopharmacology Apr 2024Prurigo nodularis (PN) is a neuroimmunological skin disease. Severe itching is the most challenging symptom which affects patients' quality of life. T helper 2-derived... (Review)
Review
BACKGROUND
Prurigo nodularis (PN) is a neuroimmunological skin disease. Severe itching is the most challenging symptom which affects patients' quality of life. T helper 2-derived cytokines, such as interleukin-31 and oncostatin M (OSM), play a crucial role in PN pathogenesis. Nemolizumab and vixarelimab are two biologics acting as IL-31 inhibitors. Vixarelimab also suppresses the OSM activity. This systematic review evaluates the efficacy and safety of nemolizumab and vixarelimab in PN management.
METHODS
A systematic search was conducted in PubMed/Medline, Ovid Embase, and Web of Science up to September 17th, 2023. Clinical trials and cohort studies published in English were included.
RESULTS
Among a total of 96 relevant records, five were included. The results of four studies with 452 patients using nemolizumab showed that a significantly higher percentage of patients treated with nemolizumab demonstrated a reduction in peak pruritus numerical rating scale (PP-NRS) and investigator's global assessment along with improved sleep disturbance (SD) and quality of life than the placebo group. Moreover, one study administered vixarelimab to 49 PN patients, and their finding illustrated a higher rate of subjects who received vixarelimab experienced ≥ 4-point diminution in worst itch NRS, visual analog scale, healing of representative lesions, and SD quality compared to the placebo group.
CONCLUSIONS
IL-31 inhibitors suggest distinct advantages in improving pruritus, sleep quality, and overall quality of life in subjects with moderate-to-severe PN. Further clinical studies are recommended to compare the effectiveness of these biologics to other therapeutic choices.
Topics: Humans; Biological Products; Interleukin Inhibitors; Prurigo; Pruritus; Quality of Life; Interleukins
PubMed: 38332383
DOI: 10.1007/s10787-024-01436-9 -
World Journal of Gastrointestinal... Jan 2024Oncostatin M (OSM) is a pleiotropic cytokine which is implicated in the pathogenesis of inflammatory bowel disease (IBD).
BACKGROUND
Oncostatin M (OSM) is a pleiotropic cytokine which is implicated in the pathogenesis of inflammatory bowel disease (IBD).
AIM
To evaluate the prognostic role of OSM in IBD patients.
METHODS
Literature search was conducted in electronic databases (Google Scholar, Embase, PubMed, Science Direct, Springer, and Wiley). Studies were selected if they reported prognostic information about OSM in IBD patients. Outcome data were synthesized, and meta-analyses were performed to estimate standardized mean differences (SMDs) in OSM levels between treatment responders and non-responders and to seek overall correlations of OSM with other inflammatory biomarkers.
RESULTS
Sixteen studies (818 Crohn's disease and 686 ulcerative colitis patients treated with anti-tumor necrosis factor-based therapies) were included. OSM levels were associated with IBD severity. A meta-analysis found significantly higher OSM levels in non-responders than in responders to therapy [SMD 0.80 (0.33, 1.27); = 0.001], in non-remitters than in remitters [SMD 0.75 (95%CI: 0.35 to 1.16); < 0.0001] and in patients with no mucosal healing than in those with mucosal healing [SMD 0.63 (0.30, 0.95); < 0.0001]. Area under receiver operator curve values showed considerable variability between studies but in general higher OSM levels were associated with poor prognosis. OSM had significant correlations with Simple Endoscopic Score of Crohn's disease [ = 0.47 (95%CI: 0.25 to 0.64); < 0.0001], Mayo Endoscopic Score [ = 0.35 (95%CI: 0.28 to 0.41); < 0.0001], fecal calprotectin [ = 0.19 (95%CI: 0.08 to 0.3); = 0.001], C-reactive protein [ = 0.25 (95%CI: 0.11 to 0.39); < 0.0001], and platelet count [ = 0.28 (95%CI: 0.17 to 0.39); < 0.0001].
CONCLUSION
OSM is a potential candidate for determining the severity of disease and predicting the outcomes of anti-tumor necrosis factor-based therapies in IBD patients.
PubMed: 38328320
DOI: 10.4240/wjgs.v16.i1.228 -
Talanta May 2024Oncostatin M (OSM) is an interleukin-6 (IL-6) member family cytokine implicated in the pathogenesis of chronic diseases including inflammatory bowel disease (IBD). OSM...
Oncostatin M (OSM) is an interleukin-6 (IL-6) member family cytokine implicated in the pathogenesis of chronic diseases including inflammatory bowel disease (IBD). OSM is a novel diagnostic biomarker over-expressed in the serum of IBD patients. This paper reports on the first electrochemical OSM immunosensor, developed using a multistep fabrication process aimed at covalently immobilizing OSM antibodies on a mixed self-assembled monolayer coated gold working electrode. Cyclic voltammetry, atomic force microscopy (AFM), IR spectroscopy and optical characterizations were used to validate the sensor functionalization protocol. Electrochemical impedance spectroscopy (EIS) measurements were performed to assess the reliability of the immunosensor preparation and to verify the antibody-antigen complexes formation. The label-free immunosensor showed high sensitivity identifying OSM at clinically relevant concentrations (37-1000 pg mL) with low detection limit of 2.86 pg mL. Both sensitivity and selectivity of the proposed immunosensor were also demonstrated in human serum in the presence of interfering biomarkers, making it an innovative potential platform for the OSM biomarker detection in IBD patients' serum.
Topics: Humans; Biosensing Techniques; Oncostatin M; Reproducibility of Results; Antibodies, Immobilized; Immunoassay; Biomarkers; Inflammatory Bowel Diseases
PubMed: 38316076
DOI: 10.1016/j.talanta.2024.125726 -
Journal of the Canadian Association of... Feb 2024Crohn's disease (CD), a chronic inflammatory condition of the digestive tract, poses significant challenges in terms of disease prognosis and treatment selection.... (Review)
Review
Crohn's disease (CD), a chronic inflammatory condition of the digestive tract, poses significant challenges in terms of disease prognosis and treatment selection. Biomarkers have the potential to predict CD outcomes and guide clinical decision-making. This review aims to summarize the current literature on promising biomarkers associated with CD outcomes and their potential clinical implications. The identification of reliable biomarkers for CD outcomes is of paramount importance in tailoring treatment strategies, monitoring disease activity, and predicting the risk of complications. Clinical prognostic factors traditionally used to assess disease severity, and the likelihood of complications have limitations in accuracy and predictive value. Thus, there is a need for more precise biomarkers, particularly in newly diagnosed and treatment-naive patients. Pharmacogenomic markers, such as TPMT and NUDT15 polymorphisms, have been utilized to identify patients at risk of adverse events with thiopurine therapy. Several biomarkers, including HLA haplotypes, oncostatin M expression, and transcriptomic profiles, have shown associations with response to anti-TNF therapy. Confocal laser endomicroscopy and single-cell analyses hold promise in predicting treatment response to specific therapies. The identification of biomarkers associated with post-operative recurrence in CD is crucial, as it could lead to changes in management algorithms. Several promising microbiome signatures and proteomic profiles have been identified. In conclusion, biomarkers have the potential to revolutionize the management of CD by providing valuable prognostic information and guiding treatment decisions. However, further research and validation are necessary to establish their clinical utility and integration into routine practice.
PubMed: 38314176
DOI: 10.1093/jcag/gwad024 -
ACS Applied Materials & Interfaces Feb 2024Cranial bone defects remain a major clinical challenge, increasing patients' life burdens. Tricarboxylic acid (TCA) cycle metabolites play crucial roles in facilitating...
Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated Mesenchymal Stem Cell Recruitment and Histone Acetylation-Mediated Osteogenesis.
Cranial bone defects remain a major clinical challenge, increasing patients' life burdens. Tricarboxylic acid (TCA) cycle metabolites play crucial roles in facilitating bone tissue regeneration. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration still needs to be improved. The mechanism underlying the release of TCA cycle metabolites from biomaterials in regulating immune responses and mesenchymal stem cell (MSC) fate (migration and differentiation) remains unknown. Herein, this work constructs biomimetic hydrogels composed of gelatin and chitosan networks covalently cross-linked by genipin (CGG hydrogels). A series of TCA cycle metabolite-coordinated CGG hydrogels with strong mechanical and antiswelling performances are subsequently developed. Remarkably, the citrate (NaCit, Cit)-coordinated CGG hydrogels (CGG-Cit hydrogels) with the highest mechanical modulus and strength significantly promote skull bone regeneration in rat and murine cranial defects. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, this work demonstrates that CGG-Cit hydrogels promote Gli1 MSC migration via neutrophil-secreted oncostatin M. Results also indicate that citrate improves osteogenesis via enhanced histone H3K9 acetylation on osteogenic master genes. Taken together, the immune microenvironment- and MSC fate-regulated CGG-Cit hydrogels represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.
Topics: Humans; Rats; Mice; Animals; Osteogenesis; Histones; Citric Acid Cycle; Acetylation; Neutrophils; Bone Regeneration; Mesenchymal Stem Cells; Skull; Cell Differentiation; Hydrogels; Citrates
PubMed: 38284176
DOI: 10.1021/acsami.3c15473 -
The Journal of Clinical Investigation Jan 2024Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor...
Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Interleukin-6; Oncostatin M; Cell Plasticity; Cell Line, Tumor; Neoplasm Recurrence, Local; Lung Neoplasms; Neoplasms, Second Primary; Spinocerebellar Ataxias; Neoplasm Metastasis; Tumor Microenvironment
PubMed: 38236642
DOI: 10.1172/JCI166847 -
Journal of Interferon & Cytokine... Feb 2024Nine soluble ligands [interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF),... (Review)
Review
Nine soluble ligands [interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine, interleukin-27 (IL-27), and interleukin-31] share the ubiquitously expressed transmembrane protein-glycoprotein-130 beta-subunit (gp130) and thus form IL-6 family cytokines. Proteins that may be important for cancerogenesis, CT-1, IL-11, IL-27, LIF, OSM, and CNTF, belong to the superfamily of IL-6. Cytokines such as IL-6, IL-11, and IL-27 are better investigated in comparison with other members of the same family of cytokines, eg, CT-1. Gp130 is one of the main receptors through which these cytokines exert their effects. The clinical implication of understanding the pathways of these cytokines in oncology is that targeted therapy to inhibit or potentiate cytokine activity may lead to remission in some cases.
Topics: Humans; Interleukin-6; Interleukin-11; Cytokine Receptor gp130; Ciliary Neurotrophic Factor; Interleukin-27; Receptors, Cytokine; Growth Inhibitors; Cytokines; Neoplasms
PubMed: 38232478
DOI: 10.1089/jir.2023.0103