Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to function in a range of pathological conditions, such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodeling following AMI. Following AMI in mice, MDSCs frequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following the adoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-ß1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-ß1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly, blockade of IL-10 partially abolished the cardioprotective role of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

Temporal Immune Profiling in the CSF and Blood of Patients with Aneurysmal Subarachnoid Hemorrhage.

Background: Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset. Methods: Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. Peripheral blood mononuclear cells (PBMCs) were collected and their cytokine production quantified following stimulation. Results: Mixed-effects models revealed distinct immune cell dynamics in CSF compared to blood. Natural killer T cell frequency increased over time in CSF only, while monocyte/macrophage numbers increased in both CSF and PBMCs. CD4+ HLA II+ T cells increased in circulation. Unstimulated PBMCs showed increased IL-1ß, IL-6, and TNFα production, peaking at 7 days post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 days post-injury, preceding immune cell profile alterations. Conclusions: Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a promising therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.

IL-10 deficiency aggravates cell senescence and accelerates BLM-induced pulmonary fibrosis in aged mice via PTEN/AKT/ERK pathway.

BACKGROUND: Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF. METHODS: Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-ß-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways. RESULTS: The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-ß-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins. CONCLUSIONS: IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF.

Elevated Interleukin-6 Is Associated with Successful Weight Loss 3 Months Postlaparoscopic Sleeve Gastrectomy.

PURPOSE: Bariatric surgery poses an ever-increasing importance in the effective and long-lasting treatment of obesity, a condition strongly associated with inflammation and increased risk of other diseases and health problems. In obesity-related inflammation, maintaining a balance between pro-inflammatory and anti-inflammatory cytokines is crucial. In this study, we examined early effects of laparoscopic sleeve gastrectomy (LSG) on inflammatory and anti-inflammatory cytokines in obese patients, and assessed their effect on postoperative weight loss. MATERIALS AND METHODS: This prospective cohort study was conducted from September 2022 till June 2023. Fifty obese adults were enrolled for LSG. All patients underwent assessments of body measurements, as well as levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and TNF-alpha at baseline and 3 months postsurgery. We developed a decision tree model to predict the success of weight loss. RESULTS: At 3 months postsurgery, patients lost 18.9 ± 6.9 kg of excess body weight. A significant decrease was observed for IL-10 (p < 0.0001), simultaneously with a significant increase in IL-6 (p < 0.0001). We found that high IL-6 (> 1.169 pg/mL) levels could contribute to an effective weight loss among patients with a baseline BMI less than 47.46 kg/m2. CONCLUSION: Study revealed that 3 months after bariatric surgery, inflammation persists, and its markers significantly influence postoperative weight loss, as indicated by BMI range. Distinct behaviors of IL-10 and IL-6 in relation to obesity underline the necessity of considering individual cytokine profiles when evaluating bariatric surgery outcomes.

Conventional and Novel Inflammatory Biomarkers in Chronic Heart Failure Patients with Atrial Fibrillation.

(1) Background and Objectives: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity and mortality both in the general population and heart failure patients. Inflammation may promote the initiation, maintenance and perpetuation of AF, but the impact of inflammatory molecular signaling on the association between AF and heart failure remains elusive. (2) Materials and Methods: In 111 patients with chronic stable heart failure, baseline values of conventional (IL-6 and hsCRP) and selected novel inflammatory biomarkers (IL-10, IL-6/IL-10 ratio, orosomucoid and endocan) were determined. Inflammatory biomarkers were compared with respect to the presenting cardiac rhythm. (3) Results: Patients aged below 75 years with AF had significantly higher values of IL-6 and IL-6/IL-10 ratio; IL-6 levels were a significant predictor of AF in both univariate (OR 1.175; 95%CI 1.013-1.363; p = 0.034) and multivariate logistic regression analysis when accounting for other inflammatory biomarkers (OR 1.327; 95% CI 1.068-1.650; p = 0.011). Conversely, there was no association between other novel inflammatory biomarkers and AF. (4) Conclusions: IL-6 levels and the IL-6/IL-10 ratio are associated with AF in patients with chronic stable heart failure under the age of 75 years, suggesting that inflammatory molecular signaling may play a role in the development of AF in the heart failure population.

Impacts of Interleukin-10 Promoter Genotypes on Prostate Cancer.

Prostate cancer (PCa) is a multifactorial disease influenced by genetic, environmental, and immunological factors. Genetic polymorphisms in the interleukin-10 (IL-10) gene have been implicated in PCa susceptibility, development, and progression. This study aims to assess the contributions of three IL-10 promoter single nucleotide polymorphisms (SNPs), A-1082G (rs1800896), T-819C (rs3021097), and A-592C (rs1800872), to the risk of PCa in Taiwan. The three IL-10 genotypes were determined using PCR-RFLP methodology and were evaluated for their contributions to PCa risk among 218 PCa patients and 436 non-PCa controls. None of the three IL-10 SNPs were significantly associated with the risks of PCa (p all > 0.05) in the overall analyses. However, the GG at rs1800896 combined with smoking behavior was found to significantly increase the risk of PCa by 3.90-fold (95% confidence interval [95% CI] = 1.28-11.89, p = 0.0231). In addition, the rs1800896 AG and GGs were found to be correlated with the late stages of PCa (odds ratio [OR] = 1.90 and 6.42, 95% CI = 1.05-3.45 and 2.30-17.89, p = 0.0452 and 0.0003, respectively). The IL-10 promoter SNP, A-1082G (rs1800896), might be a risk factor for PCa development among smokers and those at late stages of the disease. These findings should be validated in larger and more diverse populations.

[Clinical Analysis of PD-1 Inhibitor Combined with Lenalidomide in Treatment of Relapsed CD5+ Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To investigate the clinical characteristics and treatment of relapsed CD5+ diffuse large B-cell lymphoma (DLBCL). METHODS: The data of a patient with CD5+ DLBCL was collected, and its clinical characteristics and treatment outcome were analyzed. RESULTS: The patient developed hemophagocytic syndrome and achieved complete remission (CR) after 6 cycles of R-ECHOP chemotherapy, then relapsed. After 2 cycles of PD-1 inhibitor combined with lenalidomide treatment, the patient achieved CR again accompanied by a decrease of interleukin (IL)-10 expression level. After a total of 15 cycles of chemotherapy, the patient remained in CR for 24 months, and the level of IL-10 remained in the normal range. CONCLUSION: PD-1 inhibitor combined with lenalidomide regimen may be a new treatment for relapsed CD5+ DLBCL.

Different mechanisms guide the antinociceptive effect of bone marrow-mononuclear cells and bone marrow-mesenchymal stem/stromal cells in trigeminal neuralgia.

AIMS: Trigeminal neuralgia (TN) is a type of chronic orofacial pain evoked by trivial stimuli that manifests as episodes of excruciating and sudden, recurrent paroxysmal pain. Most patients are refractory to pharmacological therapy used for the treatment of TN. Mononuclear cells (MNC) and mesenchymal stem/stromal cells (MSC) have shown therapeutic potential in painful neuropathies, but their mechanism of action is not fully understood. The present work aimed to investigate the antinociceptive effect and mechanism of action of MNC and MSC in experimental TN. MATERIALS AND METHODS: Mice submitted to the chronic constriction injury of the infraorbital nerve (CCI-ION) mouse model of TN received a single intravenous injection of saline, MNC, or MSC (1 × 106 cells/mouse). The effect of the treatments on the behavioral signs of painful neuropathy, morphological aspects of the infraorbital nerve, and inflammatory and oxidative stress markers in the infraorbital nerve were assessed. KEY FINDINGS: MNC and MSC improved behavioral painful neuropathy, activated key cell signaling antioxidant pathways by increasing Nrf2 expression, and reduced the proinflammatory cytokines IL-1ß and TNF-α. However, treatment with MSC, but not MNC, was associated with a sustained increase of IL-10 and with the re-establishment of the morphometric pattern of the infraorbital nerve, indicating a difference in the mechanism of action between MNC and MSC. In line with this result, in IL-10 knockout mice, MSC transplantation did not induce an antinociceptive effect. SIGNIFICANCE: Importantly, these data suggest an IL-10-induced disease-modifying profile related to MSC treatment and reinforce cell therapy's potential in treating trigeminal neuralgia.

Ascites and Serum Interleukin-10 Levels as a Prognostic Tool for Ovarian Cancer Outcomes.

Interleukin-10 (IL-10) has been shown to be present at high levels in the ascites of ovarian cancer (OC) patients; however, little is known about its prognostic value. We sought to correlate IL-10 levels in ascites and sera of OC patients with clinicopathologic characteristics and oncologic outcomes. IL-10 levels and clinical data from biobanked ascites and serum samples of OC patients were evaluated. Receiver operating characteristic curves were used to quantify marker performance and identify IL-10-high and IL-10-low groups. Correlations between IL-10 levels and clinicopathologic data were performed. Survival outcomes were calculated, while the factors affecting them were also investigated. A total of 106 patients had ascites samples, of which 44 serum samples were also available. Mean ascites IL-10 levels were significantly higher in patients with serous histology compared to endometrioid histology (p = 0.024). Fold-change in ascites IL-10 during treatment positively correlated with clinical response, as determined by a change in serum cancer antigen (CA)-125 levels (p = 0.0126). Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with high compared with low ascites IL-10 levels (PFS: 18 versus 60 months; p = 0.007, OS: 42 versus 85 months; p = 0.029). A significant positive correlation was seen between ascites and sera IL-10 levels (p = 0.019). In multivariable analyses, a high ascites IL-10 level was associated with a significantly worse prognosis (PFS hazard ratio (HR) = 1.93; p = 0.02). Patients with high ascites levels of IL-10 have worse outcomes, which are likely reflective of the immunosuppressive effect of IL-10. This highlights its potential role as an immunomodulator in the tumor microenvironment, leading to OC immune evasion.

Levilactobacillus brevis IBARAKI-TS3 Isolated From Pickles Promotes Production of Interleukin-10 via Toll-Like Receptor 2 in Human M2 Macrophages.

M2 macrophages play an important role in food allergy. Several studies have reported that lactic acid bacteria isolated from pickles exert antiallergic effects. We investigated the effects of several strains of lactic acid bacteria on the immune function of M2 macrophages. M2 macrophages differentiated from THP-1 cell line by interleukin-4 (IL-4) and IL-13 strongly expressed CD163, CD206, and HMOX1 mRNA. Levilactobacillus brevis IBARAKI-TS3 (IBARAKI-TS3) isolated from pickles was identified as a lactic acid bacterium that enhances the expressions of IL-10 and EBI3 mRNA in M2 macrophages. IBARAKI-TS3 induced the expression of genes involved in Toll-like receptor (TLR) signaling, such as IRAK, mitogen-activated protein kinases (MAPKs), and NF-κB mRNA. IBARAKI-TS3-induced IL-10 production was suppressed by anti-TLR2-neutralizing antibodies. Furthermore, the IBARAKI-TS3-induced increase in IL-10 levels was significantly reduced in TLR2-knockdown M2 macrophages compared to M2 macrophages. These results suggest that IBARAKI-TS3 promotes of IL-10 production via TLR2 in M2 macrophages.

Dexmedetomidine induces IL-10 secretion by B lymphocytes in the peripheral blood of patients with hepatocellular carcinoma.

BACKGROUND/AIM: To investigate the distribution of subpopulations of peripheral blood B lymphocytes in individuals with hepatocellular carcinoma (HCC), and to evaluate the effect of dexmedetomidine (DEX) on B lymphocyte differentiation in patients with HCC in vitro. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from the HCC group and the healthy group, and the distribution of peripheral blood B-lymphocyte subpopulations in the two groups was examined by Flow Cytometry (FCM). B lymphocytes extracted from the peripheral blood of the HCC group were divided into D0, D1, D2 and D4 groups according to the different dose of DEX in the culture medium (0 µM, 1 µM, 2 µM and 4 µM). After 72 h of in vitro culture, FCM was used to detect differences in the percentage of apoptotic B lymphocytes and the percentage of B lymphocytes that can express interleukin 10(IL-10) and transforming growth factor-ß (TGF-ß) in each group. RESULTS: In contrast to the healthy group, the HCC group exhibited a statistically significant increase in the proportion of CD19 + CD73 + B lymphocyte subpopulation (P<0.05). In the in vitro culture experiment, the differences in apoptosis of B lymphocytes and the percentage of TGF-ß expression in each group were not statistically significant; When compared to the control group, there was a significant increase in the percentage of B lymphocytes expressing IL-10 across the D1, D2, and D4 groups (P<0.05). CONCLUSION: The peripheral blood of HCC patients is characterized by an elevated presence of CD19 + CD73 + B lymphocyte subpopulations; DEX may have an immunosuppressive effect by promoting IL-10 secretion from peripheral blood B lymphocytes of HCC patients.

CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.

BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10). METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis. CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment.

BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.

Effects of SNPs on TNF-α and IL-10 cytokine expression in TB and HIV patients in the Capricorn district, Limpopo Province, South Africa.

Background: The impact of Tuberculosis (TB) places an immense burden on the health care system. Infection with Human Immunodeficiency Virus (HIV) is a significant risk factor in the development and progression of TB disease. Single Nucleotide Polymorphisms (SNPs) in the promoter region of Interleukin-10 (IL-10) and Tumour Necrotic Factor-Alpha (TNF-α) may play a major role in the disease mechanism and understanding these mechanisms might prove to be a useful diagnostic tool in evaluating the immune regulation and progression of the disease. Objective: This study aimed to determine the relationship between cytokine levels and gene variants of Interleukin-10 and Tumour Necrotic Factor Alpha in TB and HIV-infected participants. Methods: Cytokine levels were determined by ELISA, and SNPs were determined by MassArray®. Results: The levels of TNF-α were higher in the TB group than the HIV (p < 0.001) and TB-HIV (p = 0.011) groups, but similar to the TNF-α levels in the control group. In the HIV group, IL-10 levels were higher than those of the TB (p < 0.001) and control groups (p = 0.039), whereas there was no difference between the IL-10 levels in the HIV and the TB-HIV infection groups. The ratio was determined and there were no differences between the four infection groups. In this study, no associations were detected between the circulating plasma levels of TNF-α and IL-10 and their genotypes. Conclusion: Our data showed that the gene variants were not associated with circulating plasma levels of TNF-α and IL-10 in our study population. A pro-inflammatory environment was found in the TB and TB-HIV groups, which is suggesting of bacterial clearance, while an anti-inflammatory environment was found in the HIV group, which suggests the suppression of viral replication.

Impact of IL-6 and IL-10 genotypes on tacrolimus dose requirements in kidney transplant recipients: Monte Carlo analysis.

Introduction: IL-6 and IL-10 may affect the activity of cytochrome P450 (CYP) 3A enzymes involved in tacrolimus (Tac) metabolism. Moreover, the effect of IL-6 and IL-10 on Tac pharmacokinetics may differ with respect to the genetic variations in their genes.Aim: To examine the influence of IL-6 and IL-10 gene polymorphisms on Tac dose requirements and exposure over a 5-year period following kidney transplantation. Univariate and standard multivariate linear regression and Monte Carlo analysis were performed to investigate potential covariates influencing Tac dose-adjusted trough concentration (C0/D) in various post-transplantation periods.Materials & methods: IL-6 (-174G > C), IL-10 (-1082G > A, -819C > T and -592C > A) genotype, Tac daily dose, C0, C0/D and intrapatient variability data were collected from 113 patients.Results: Multivariate regression analysis and accompanied Monte Carlo simulation underscore the importance of considering IL-6 -174G > C and IL-10 -1082G > A gene polymorphisms, alongside Tac metabolic phenotype and post-transplantation period, when tailoring Tac dosage regimen.Conclusion: This study provides valuable insights regarding the individualized adjustment of Tac treatment in various post-transplantation periods.

[Box: see text].

Preoperative Immune Cell Dysregulation Accompanies Ovarian Cancer Patients into the Postoperative Period.

Ovarian cancer (OC) poses a significant global health challenge with high mortality rates, emphasizing the need for improved treatment strategies. The immune system's role in OC progression and treatment response is increasingly recognized, particularly regarding peripheral blood mononuclear cells (PBMCs) and cytokine production. This study aimed to investigate PBMC subpopulations (T and B lymphocytes, natural killer cells, monocytes) and cytokine production, specifically interleukin-1 beta (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNFα), in monocytes of OC patients both preoperatively and during the early postoperative period. Thirteen OC patients and 23 controls were enrolled. Preoperatively, OC patients exhibited changes in PBMC subpopulations, including decreased cytotoxic T cells, increased M2 monocytes, and the disbalance of monocyte cytokine production. These alterations persisted after surgery with subtle additional changes observed in PBMC subpopulations and cytokine expression in monocytes. Considering the pivotal role of these altered cells and cytokines in OC progression, our findings suggest that OC patients experience an enhanced pro-tumorigenic environment, which persists into the early postoperative period. These findings highlight the impact of surgery on the complex interaction between the immune system and OC progression. Further investigation is needed to clarify the underlying mechanisms during this early postoperative period, which may hold potential for interventions aimed at improving OC management.

Logistic regression modeling of cytokines for cerebrospinal fluid evaluation in primary central nervous system lymphoma.

BACKGROUND: The diagnostic utility of cerebrospinal fluid (CSF) cytology encounters impediments stemming from variability in cell collection techniques and pathologists' morphological acumen, resulting in wide-ranging CSF positivity rates for primary central nervous system lymphomas (PCNSL). Such disparity impacts patient evaluation, treatment stratagem, and prognostication. Thus, this study endeavors to explore liquid biomarkers complementary to CSF cytology or immunophenotype analysis in the diagnosis of CSF involvement. METHODS: 398 newly diagnosed PCNSL patients were categorized into CSF involvement and non-involvement groups based on CSF cytology and immunophenotype analysis. Binary logistic regression analysis was performed on 338 patients to investigate factors predicting CSF involvement and to develop a joint prediction model. An additional cohort of 60 PCNSL patients was recruited for model validation. Statistical analyses included the Mann-Whitney U test for comparing various CSF parameters between two groups. ROC curve analyses were performed for each biomarker to identify PCNSL CSF involvement. RESULTS: The cytokine IL-10 level in CSF has emerged as the most promising biomarker for CSF evaluation, boasting an ROC AUC of 0.922. C-TNFα and soluble C-IL2R demonstrate efficacy in quantifying tumor burden within the CSF. Logistic regression identified C-IL10lg (OR = 30.103, P < 0.001), C-TNC (OR = 1.126, P < 0.001), C-IL2Rlg (OR = 3.743, P = 0.029) as independent predictors for CSF involvement, contributing to a joint predictive model with an AUC of 0.935, sensitivity of 74.1 %, and specificity of 93.0 %. Validation of the model in an independent cohort confirmed its effectiveness, achieving an AUC of 0.9713. CONCLUSIONS: The identification of these feasible biomarkers and the development of an accurate prediction model may facilitate the precise evaluation of CSF status in PCNSL, offering significant advancements in patient management.

The role of interleukin-10 receptor alpha (IL10Rα) in Mycobacterium avium subsp. paratuberculosis infection of a mammary epithelial cell line.

BACKGROUND: Johne's disease is a chronic wasting disease caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease is highly contagious and MAP infection in dairy cattle can eventually lead to death. With no available treatment for Johne's disease, genetic selection and improvements in management practices could help reduce its prevalence. In a previous study, the gene coding interleukin-10 receptor subunit alpha (IL10Rα) was associated with Johne's disease in dairy cattle. Our objective was to determine how IL10Rα affects the pathogenesis of MAP by examining the effect of a live MAP challenge on a mammary epithelial cell line (MAC-T) that had IL10Rα knocked out using CRISPR/cas9. The wild type and the IL10Rα knockout MAC-T cell lines were exposed to live MAP bacteria for 72 h. Thereafter, mRNA was extracted from infected and uninfected cells. Differentially expressed genes were compared between the wild type and the IL10Rα knockout cell lines. Gene ontology was performed based on the differentially expressed genes to determine which biological pathways were involved. RESULTS: Immune system processes pathways were targeted to determine the effect of IL10Rα on the response to MAP infection. There was a difference in immune response between the wild type and IL10Rα knockout MAC-T cell lines, and less difference in immune response between infected and not infected IL10Rα knockout MAC-T cells, indicating IL10Rα plays an important role in the progression of MAP infection. Additionally, these comparisons allowed us to identify other genes involved in inflammation-mediated chemokine and cytokine signalling, interleukin signalling and toll-like receptor pathways. CONCLUSIONS: Identifying differentially expressed genes in wild type and ILR10α knockout MAC-T cells infected with live MAP bacteria provided further evidence that IL10Rα contributes to mounting an immune response to MAP infection and allowed us to identify additional potential candidate genes involved in this process. We found there was a complex immune response during MAP infection that is controlled by many genes.

Peripheral cytokine interleukin-10 alleviates perihematomal edema after intracerebral hemorrhage via interleukin-10 receptor/JAK1/STAT3 signaling.

AIMS: The extent of perihematomal edema following intracerebral hemorrhage (ICH) significantly impacts patient prognosis, and disruption of the blood-brain barrier (BBB) exacerbates perihematomal edema. However, the role of peripheral IL-10 in mitigating BBB disruption through pathways that link peripheral and central nervous system signals remains poorly understood. METHODS: Recombinant IL-10 was administered to ICH model mice via caudal vein injection, an IL-10-inhibiting adeno-associated virus and an IL-10 receptor knockout plasmid were delivered intraventricularly, and neurobehavioral deficits, perihematomal edema, BBB disruption, and the expression of JAK1 and STAT3 were evaluated. RESULTS: Our study demonstrated that the peripheral cytokine IL-10 mitigated BBB breakdown, perihematomal edema, and neurobehavioral deficits after ICH and that IL-10 deficiency reversed these effects, likely through the IL-10R/JAK1/STAT3 signaling pathway. CONCLUSIONS: Peripheral IL-10 has the potential to reduce BBB damage and perihematomal edema following ICH and improve patient prognosis.

Interleukin-10 induces TNF-driven apoptosis and ROS production in salivary gland cancer cells.

Treatment resistance after chemo-/immunotherapy occurs in patients with head and neck squamous cell cancers (HNSCs), including salivary gland cancers (SGCs). Interleukin-10 (IL-10), a cytokine with pro- and anti-cancer effects, has an unclear impact on HNSC/SGC cells. We show that HNSC patients exhibiting high expression of IL-10 and its receptor IL-10Rα experience have prolonged overall survival. Immunoreactive IL-10 was low in ductal cells of human SGC biopsies. Human (A253) and murine WR21-SGC cells expressed IL-10Rß, but only A253 cells expressed IL-10 and IL-10Rα. The addition of recombinant IL-10 impaired SGC cell proliferation and induced apoptosis in vitro. N-acetylcysteine restored IL-10-induced reactive oxygen species (ROS) production but did not prevent IL-10-mediated viability loss. Mechanistically, recIL-10 delayed cell cycle progression from G0/G1 to the S phase with cyclin D downregulation and upregulation of NF-kB. IL-10 increased tumor necrosis factor-α (TNF-α) in A253 and WR21 and FasL in WR21 cells. Neutralizing antibodies against TNF-α and NF-kB inhibition restored SGC proliferation after IL-10 treatment, emphasizing the critical role of TNF-α and NF-kB in IL-10-mediated anti-tumor effects. These findings underscore the potential of IL-10 to impede SGC cell growth through apoptosis induction, unraveling potential therapeutic targets for intervention in salivary gland carcinomas.