Cytokines Interleukin Research Articles

Correlation of serum interleukin-8 levels and prostate volume to the degree of lower urinary tract symptoms in patients with benign prostate enlargement: a cross-sectional study

BackgroundBenign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) are pro-inflammatory cytokine interleukin-8 (IL-8)-associated which causes epithelial hyperplasia of the prostate transitional zone. This study aimed to determine the correlation between the levels of IL-8 serum and the prostate volume with the degree of LUTS severity in patients with BPE.MethodsDetermination of the correlation between serum IL-8 levels and prostate volume with the LUTS severity degree was conducted using a cross-sectional approach. The International Prostate Symptom Score was used to measure the LUTS severity degree, the enzyme-linked immunosorbent assay (ELISA) technique was used to measure the serum IL-8 level, and the transabdominal ultrasonography (TAUS) was used to measure the prostate volume. The sample used in this study was 32 patients with BPE grouped by the degree of LUTS severity of the patients. The correlation between variables was then analyzed using the Pearson correlation test.ResultsThe prostate volume was higher in severe LUTS degree (38.19 cc) than in the mild LUTS degree (13.05 cc). The levels of serum IL-8 were higher in the severe LUTS degree (21.65 pg/mL) than in the mild LUTS degree (8.44 pg/m). Both the levels of serum IL-8 and the degree of LUTS did not have a significant correlation with the volume of prostate (p > 0.05). On the other side, the prostate volume and the degree of LUTS severity had a significant positive correlation (p = 0.001, R = 0.913).ConclusionThe prostate volume and the levels of serum IL-8 are higher in the severe LUTS degree. There is a trend of increasing prostate volume with the severity of LUTS symptoms and higher serum IL-8 levels. The severity of prostate enlargement can be assessed by measuring the levels of IL-8 in the serum.

Regulatory B-cells: immunomodulating mechanisms and important cellular targets underlining immunotherapy by immunoregulation

Regulatory B-cells (Breg cells) represent as an important modulator of the immune system and their role is unique in autoimmunity, infection, tolerance to transplants, allergy, and cancer. Several regulatory mechanisms exist by which Breg cells can control the function of other immune cells through two main pathways: the secretion of soluble mole¬cules and the use of cell surface-expressed molecules. Anti-inflammatory cytokine interleukin-10 acts as the hallmark of Breg cell function; other cytokines with a similar role include the transforming growth factor-beta and interleukin-35. Breg B cells also release the cytotoxic granzyme B that mediates cell apoptosis. Cell surface-expressed proteins include FasL, CD80, CD86, CD73, CD1d, and PD-L1. The present article reviews the immunosuppressive pathways in order to understand how they emerge and are induced to evoke their regulatory activities, and how we can benefit from them in the field of immunotherapy.

Primary cilia abnormalities participate in the occurrence of spontaneous abortion through TGF-β/SMAD2/3 signaling pathway.

Spontaneous abortion is the most common complication in early pregnancy, the exact etiology of most cases cannot be determined. Emerging studies suggest that mutations in ciliary genes may be associated with progression of pregnancy loss. However, the involvement of primary cilia on spontaneous abortion and the underlying molecular mechanisms remains poorly understood. We observed the number and length of primary cilia were significantly decreased in decidua of spontaneous abortion in human and lipopolysaccharide (LPS)-induced abortion mice model, accompanied with increased expression of proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The length of primary cilia in human endometrial stromal cell (hESC) was significantly shortened after TNF-α treatment. Knocking down intraflagellar transport 88 (IFT88), involved in cilia formation and maintenance, promoted the expression of TNF-α. There was a reverse regulatory relationship between cilia shortening and TNF-α expression. Further research found that shortened cilia impair decidualization in hESC through transforming growth factor (TGF)-β/SMAD2/3 signaling. Primary cilia were impaired in decidua tissue of spontaneous abortion, which might be mainly caused by inflammatory injury. Primary cilia abnormalities resulted in dysregulation of TGF-β/SMAD2/3 signaling transduction and decidualization impairment, which led to spontaneous abortion.

Quantitative Analysis of Innate Lymphoid Cells in Patients with ST-Segment Elevation Myocardial Infarction

ABSTRACT Background Acute myocardial infarction (AMI) is one of the principal causes of death in Mexico and worldwide. AMI triggers an acute inflammatory process that induces the activation of different populations of the innate immune system. Innate lymphoid cells (ILCs) are an innate immunity, highly pleiotropic population, which have been observed to participate in tissue repair and polarization of the adaptive immune response. Objective We aimed to analyze the levels of subsets of ILCs in patients with ST-segment elevation myocardial infarction (STEMI), immediately 3 and 6 months post-AMI, and analyze their correlation with clinical parameters. Results We evaluated 29 STEMI patients and 15 healthy controls and analyzed the different subsets of circulating ILCs, immediately 3 and 6 months post-AMI. We observed higher levels of circulating ILCs in STEMI patients compared to control subjects and a significant correlation between ILC levels and cardiac function. We also found increased production of the cytokines interleukin 5 (IL-5) and interleukin 17A (IL-17A), produced by ILC2 cells and by ILC3 cells, respectively, in the STEMI patients. Conclusion This study shows new evidence of the role of ILCs in the pathophysiology of AMI and their possible involvement in the maintenance of cardiac function.

Interleukin-6 Modulates Action Potential Generation in Freshly Isolated Rat Dorsal Root Ganglia Neurons And its Stimulating Effect Is Exacerbated in Polycystic Kidney Disease

Our laboratory has demonstrated a central role for increased afferent nerve renal activity (ARNA) in the progression of cystogenesis in the PCK rat model of polycystic kidney disease (PKD). The underlying cause for the pathological increase in ARNA is unknown. Inflammatory cell infiltration and increased proinflammatory cytokine content, such as interleukin 6 (IL-6), have been reported in PKD. We hypothesized inflammatory cytokines directly increase sensory nerve activity, and this response is exacerbated in PKD. We measured action potential generation (AP) in freshly isolated dorsal root ganglion (DRG) neurons in PCK rats and non-cystic controls, and their response to IL-6. DRGs (T10-L1) were isolated from Sprague-Dawley (SD) or PCK rat (Age: 10-26 weeks) spinal cords, enzymatically digested and mechanically dissociated. Neurons were plated on coverslips, and AP were recorded within 24-hours (whole-cell patch-clamp). We tested the effects of IL-6 (0.04 μg/ml) and bradykinin (BK; 40μg/ml) on AP under 100, 200 pA, and 300 pA current clamp steps. IL-6 elicited either an excitatory response or inhibitory response in AP. In excitatory cells (EC), AP was normalized to BK peak response at +300 pA. In inhibited cells (IC), AP was normalized to baseline at +300 pA. PCK and IL-6 effects were assessed by two-way ANOVA (Bonferroni post hoc test;*p<.05); data as mean ± SEM. Proportion of ECs and ICs did not differ between SD and PCK rats. IL-6 increased AP at 300 pA from 0.48±0.28 (baseline) to 0.95±0.05 (p<.05) in SD ECs cells. BK further increased AP, showing no cell fatigue by IL-6 exposure. In PCK ECs, IL-6 increased AP at 100 pA (0.07±0.05 vs. 0.52±0.25), at 200 pA (0.47±0.27 vs. 1.39±0.81), and 300 pA (0.54±0.25 vs. 1.11±0.47). BK further increased AP at 100 pA to 0.70± 0.28 but decreased AP at 200 pA to 1.21±0.40 and at +300 pA to 1.00±0.00, indicating that neurons activity was likely plateaued by IL-6 at +200 and +300 pA. In both SD and PCK ICs, there was a main effect of IL-6 and BK treatment across all current steps (p<0.05). In SD ICs, IL-6 decreased AP at 200 pA (1.03±0.67 vs. 0.28±0.24) and 300 pA (1.00±0.00 vs. 0.28±0.24). BK had no effect at +200 pA and partially reversed the effect of IL-6 at +300 pA (AP increase to 0.53±0.27). In PCK ICs, IL-6 decreased AP at +200 pA (0.21±0.08 vs. 0.11±0.09) and +300 pA (1.00±0.00 vs. 0.42±0.24). BK increased AP at +200 pA (0.67±0.37) and +300 pA (0.71±0.33). These data partially support our hypothesis that IL-6 increases sensory nerve discharge. This effect was not observed uniformly across cells, as there were inhibitory and excitatory responses in both PCK and SD rats. We conclude that pro-inflammatory cytokine IL-6 can increase a subset of DRG neuron activity and responsiveness, an effect potentiated in PKD. This neuro-immune interaction might contribute to the underlying increase in ARNA and cystogenesis in PKD. Further experimentation is underway to test neuronal sensitivity to IL-6 and other inflammatory cytokines, as well as the posited potentiated effects in PKD. Supported in part by the PKD Foundation Research Award 1022534 (CB); NIDDK/PKD RRC Pilot and Feasibility Award U24DK126110 (CB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oral beta-hydroxybutyrate alleviates COVID-19 related acute respiratory distress syndrome: A randomized, single-blind, placebo-controlled trial

BackgroundAcute respiratory distress syndrome (ARDS) is a lung complication of COVID-19 that requires intensive care and ventilation. Beta-hydroxybutyrate (BHB) is a ketone body that can modulate metabolism and inflammation in immune cells and lung tissues. We hypothesized that oral BHB could alleviate COVID-19 related ARDS by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. MethodsWe randomized 75 patients with mild (as per Berlin criteria) ARDS symptoms to receive oral 25 g twice daily or placebo for five days. The primary outcome was the change in pro-inflammatory cytokines (Interleukin-1β, Interleukin-6, interleukin-18, tumour necrosis factor-alpha) and anti-inflammatory cytokine (interleukin-10) from baseline to day 5. The secondary outcomes were the change in BHB levels from baseline to day 5, the number of hospitalization days, and the occurrence of adverse events. ResultsTreatment with formulated BHB resulted in a significant decrease in pro-inflammatory cytokines; Interleukin-1β (p = 0.0204), Interleukin-6 (p = 0.0309), interleukin-18 (p = 0.0116), tumour necrosis factor-alpha (p = 0.0489) and increase in interleukin-10 (p = 0.0246) compared treatment with placebo. Importantly, higher BHB levels (p = 0.0001) were observed after supplementation; additionally, patients who underwent this approach were hospitalized for fewer days. No serious adverse events were reported. ConclusionBeta-hydroxybutyrate, an oral adjunct therapy, has shown promising results in ameliorating symptoms of ARDS. This includes reduced inflammation, oxidative stress, and decreased patient fatigue levels. Further study with a large sample size is warranted to assess the potential of BHB therapy's effectiveness in reducing the development of severe illness. Clinical trial registration(http://ctri.nic.in/CTRI/2021/03/031790)

Th1/Th2 cytokines in early peripheral blood of patients with multiple injuries and its predictive value for SIRS: A Bioinformatic Analysis

This study aims to evaluate the changes in helper T lymphocyte (Th)1/Th2 factor levels in peripheral blood of patients with severe multiple injuries and their prognostic value for nosocomial infection using bioinformatic analysis. The experimental group consisted of 180 patients with numerous injuries admitted to our hospital between January 2021 and June 2023, with 80 healthy volunteers serving as controls. Th1 cytokines (interleukin-2 and interferon-γ) and Th2 cytokines (IL-4 and IL-10) were evaluated 48 hours after admission using enzyme-linked immunosorbent assays. The experimental group was separated into two groups: those with systemic inflammatory response syndrome (SIRS) and those without SIRS, for cytokine analysis and SIRS incidence. Furthermore, the study examined Th1 and Th2 cytokine levels in trauma patients in various body locations within the experimental group. A receiver operating characteristic (ROC) curve analysis was performed to determine the predictive value of Th1/Th2 cytokines for SIRS incidence. The experimental group had lower IL-2 and IFN-γ levels compared to the control group, but greater levels of IL-4 and IL-10. There were no significant variations in Th1 and Th2 cytokine levels across the experimental groups. Patients with SIRS had lower levels of IL-2 and IFN-γ but greater levels of IL-4 and IL-10 compared to those without SIRS. Combined cytokine levels have a better predictive value for SIRS than individual cytokines alone. In conclusion, individuals with severe multiple injuries had a change from Th1 to Th2 cytokine profiles, which was most evident in those with SIRS. The combined cytokine levels had a substantial predictive value for SIRS incidence in this patient cohort.

Pregnane X receptor (PXR) deficiency promotes hepatocarcinogenesis via induction of Akr1c18 expression and prostaglandin F2α (PGF2α) levels

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F2α (PGF2α) and aldo–keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC.

Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification.

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.

CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-β

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 μg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

ACE2 and a Traditional Chinese Medicine Formula NRICM101 Could Alleviate the Inflammation and Pathogenic Process of Acute Lung Injury

The coronavirus disease 2019 (COVID-19) is a highly transmittable respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and acute lung injury (ALI) is the major complication of COVID-19. The challenge in studying SARS-CoV-2 pathogenicity is the limited availability of animal model. Therefore, it is necessary to establish animal models that can reproduce multiple characteristics of ALI to study therapeutic application. The present study established a mouse model that has features of ALI that are similar to COVID-19 syndrome to investigate the role of human angiotensin-converting enzyme type II (ACE2) and the administration of the Chinese herbal prescription Chingguan Yihau (NRICM101) in ALI. The mice with ACE2 genetic modifications, including the overexpression of human ACE2 (K18-hACE2 TG) and the absence of ACE2 (mACE2 KO), were intratracheally instillated with hydrochloric acid to induce ALI. The acid intratracheal instillation induced the imbalance between angiotensin-converting enzyme (ACE) and ACE2 (i.e., ACE/ACE2), severe immune cell infiltration, cytokine storms, inflammatory effect, and pulmonary disease in the mice. Compared with K18-hACE2 TG mice, mACE2 KO mice exhibited dramatically increased levels of multiple inflammatory cytokines Interleukin-6 (IL-6) and Tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid, histological evidence of lung injury, the production of the ACE expression, and the activation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expression. The results indicate that overproduction of ACE2 and induction of the ACE2-Ang-(1-7)/Mas axis could counteract the proinflammatory effect of acid-induced ALI and effectively alleviate the pathogenic process of acid-induced ALI by regulating MAPK, p-ERK1/2, and p-STAT3 pathways and dysregulation of MMP-2/MMP-9 activation. In addition, NRICM101, which is an effective TCM that has both antiviral and anti-inflammatory effects against COVID-19, shows potential for treating acid-induced ALI. NRICM101 could alleviate the disease progression of acid-induced ALI by suppressing IL-6 and TNF-α production in alveoli. In conclusion, the established mouse model provided an effective platform for researchers to investigate the role of ACE2 on pathological mechanisms and develop therapeutic strategies for ALI, including COVID-19-related pulmonary diseases. The effects of NRICM101 administration is a potential strategy for curing acid-induced ALI evaluated in the mouse model in this study. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fibroblast-derived interleukin-6 exacerbates adverse cardiac remodeling after myocardial infarction.

Myocardial infarction is one of the leading causes of mortality globally. Currently, the pleiotropic inflammatory cytokine interleukin-6 (IL-6) is considered to be intimately related to the severity of myocardial injury during myocardial infarction. Interventions targeting IL-6 are a promising therapeutic option for myocardial infarction, but the underlying molecular mechanisms are not well understood. Here, we report the novel role of IL-6 in regulating adverse cardiac remodeling mediated by fibroblasts in a mouse model of myocardial infarction. It was found that the elevated expression of IL-6 in myocardium and cardiac fibroblasts was observed after myocardial infarction. Further, fibroblast-specific knockdown of Il6 significantly attenuated cardiac fibrosis and adverse cardiac remodeling and preserved cardiac function induced by myocardial infarction. Mechanistically, the role of Il6 contributing to cardiac fibrosis depends on signal transduction and activation of transcription (STAT)3 signaling activation. Additionally, Stat3 binds to the Il11 promoter region and contributes to the increased expression of Il11, which exacerbates cardiac fibrosis. In conclusion, these results suggest a novel role for IL-6 derived from fibroblasts in mediating Stat3 activation and substantially augmented Il11 expression in promoting cardiac fibrosis, highlighting its potential as a therapeutic target for cardiac fibrosis.

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (β±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Da-Jian-Zhong decoction alleviates diarrhea-predominant irritable bowel syndrome via modulation of gut microbiota and Th17/Treg balance

Ethnopharmacological relevanceDa-Jian-Zhong decoction (DJZD) is a herbal formula clinically used for abdominal pain and diarrhea induced by spleen-Yang deficiency syndrome. Recently, treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) with DJZD has received increasing attention, but the underlying mechanism of action remains elusive. Aim of the studyWe aimed to evaluate the therapeutic effect of DJZD on IBS-D rats and to elucidate the underlying mechanisms. Materials and methodsAn IBS-D rats model was constructed using a two-factor superposition method of neonatal maternal separation and Senna folium aqueous extract lavage. Moreover, the effect of DJZD was evaluated based on the body weight, rectal temperature, abdominal withdrawal reflex (AWR), and Bristol stool scale score (BSS). The factors that regulate the DJZD effects on IBS-D were estimated using whole microbial genome, transcriptome sequencing (RNA-Seq), flow cytometry, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analyses. ResultsWe found that DJZD alleviated the symptoms of IBS-D rats, with the low-dose (2.4 g/kg) as the better ones, as shown by the higher body mass and lower AWR score and BSS. At the phylum level, the relative abundance of Bacteroidetes was obviously increased, and at the genus level, Bacteroides was increased, while that of Firmicutes_bacterium_424 and Ruminococcus gnavus was decreased in DJZD group. The significantly enriched GO terms after treatment with DJZD mainly included the immune response, positive regulation of activated T cell proliferation, and positive regulation of interleukin-17 (IL-17) production. Importantly, flow cytometry analysis further revealed that the T helper cell type 17/regulatory T cell (Th17/Treg) balance contributed to the DJZD-induced alleviation of IBS-D symptoms, as DJZD downregulated Th17/Treg ratio and Th17 cell-related cytokines IL-17 and IL-6 levels in the colon. ConclusionsThese results demonstrate that DJZD has a good therapeutic effect on IBS-D rats, probably by maintaining the homeostasis of gut microbiota and regulating Th17/Treg balance and its related inflammatory factors.

Interleukin-10 supplementation protects against oxalate-mediated injury in mouse kidneys and bone-marrow derived macrophages

Approximately 10% of the United States population will experience a kidney stone (KS). Dietary oxalate promotes calcium oxalate (CaOx) crystals, which are precursors to CaOx KS. Macrophages rely on Interleukin-10 (IL-10) anti-inflammatory cytokine signaling to phagocytose and remove CaOx crystals. We recently reported that oxalate causes macrophages to become M1-like (pro-inflammatory) as well as have increased Interleukin-6 (IL-6; pro-inflammatory) and reduced IL-10 cytokine secretion. The purpose of this study was to assess the effects of IL-10 supplementation on mouse kidneys and bone-marrow derived macrophages exposed to oxalate. We hypothesized that exogenous IL-10 treatment prevents oxalate-mediated injury in mouse kidneys and bone-marrow derived macrophages (BMDMs). Mice with a C57BL/6 background were fed Hydroxy-L-proline (HLP; an oxalate precursor) for 7 or 14 days ± IL-10 intraperitoneal injections (25 μg/kg for 2 days) before collecting kidneys and BMDMs. Real-Time Quantitative Reverse Transcription PCR, fluorescence assays, and histological analyses were performed. Mice fed HLP had increased IL-6 and M1 macrophage expression in their kidneys over time. These mice also had reduced IL-10 and M2 macrophage gene expression. In contrast, mice fed HLP with IL-10 supplementation had increased M2 macrophage levels as well as reduced inflammation in their kidneys. Consistent with these findings, BMDM isolated from mice fed HLP displayed similar results. These cells also had reduced mitochondrial membrane polarization and lysosomal staining and increased cellular ROS; whereas, exogenous IL-10 treatment protected BMDMs from oxalate mediated injury. These findings suggest that IL-10 signaling may be important for preventing oxalate-induced injury and inflammation in mouse kidneys and BMDMs. NIH R01 DK129885 (TM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ST2 levels and neurodegenerative diseases: is this a significant relation?

Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.

Prognostic properties of biomarkers in COVID-19 infection and concomitant chronic coronary syndromes

Background. The novel coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an unprecedented challenge for the health care system and has taken a leading position among infectious diseases due to the rapid spread and development of complications from various body systems. The problem of cardiac comorbidity in COVID-19 has several aspects: the impact of concomitant cardiovascular diseases on the incidence of a new viral infection, its severity and risk of mortality, as well as possible side effects of a number of drugs traditionally used to treat certain types of cardiovascular diseases. SARS-CoV-2 is not only a pneumonia pathogen, but also causes serious systemic consequences. Patients with cardiovascular diseases and risk factors for cardiovascular complications, such as hypertension and coronary heart disease, are more exposed to fatal consequences of COVID-19. In addition, a significant proportion of patients develop COVID-associated myocardial injury, which significantly increases the risk of in-hospital mortality. The purpose of the study was to investigate the prognostic role of individual biomarkers in patients with COVID-19-associated pneumonia on the background of chronic coronary syndromes. Materials and methods. This study was defined as an open-label, non-randomized, controlled, comparative one in parallel groups. 124 patients with COVID-19-associated pneumonia were selected upon admission, including 92 participants with a history of chronic coronary syndromes. Results. The study showed that elevated levels of biomarkers such as proinflammatory cytokine interleukin-6, iron-storage protein ferritin, serum angiotensin-converting enzyme-2, ketone body beta-hydroxybutyric acid, and fibrin breakdown product D-dimer may be associated with a more severe course of pneumonia caused by COVID-19 infection. Thus, these biomarkers had good prognostic value in predicting severe disease and death in patients with chronic coronary syndromes during hospitalization. Conclusions. The study confirms that an increase in the level of proinflammatory biomarkers is a predictor for the development of a severe coronavirus infection.

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression.

Epstein-Barr virus (EBV) persistently infects 95% of adults worldwide and is associated with multiple human lymphomas that express characteristic EBV latency programs used by the virus to navigate the B-cell compartment. Upon primary infection, the EBV latency III program, comprised of six Epstein-Barr Nuclear Antigens (EBNA) and two Latent Membrane Protein (LMP) antigens, drives infected B-cells into germinal center (GC). By incompletely understood mechanisms, GC microenvironmental cues trigger the EBV genome to switch to the latency II program, comprised of EBNA1, LMP1 and LMP2A and observed in GC-derived Hodgkin lymphoma. To gain insights into pathways and epigenetic mechanisms that control EBV latency reprogramming as EBV-infected B-cells encounter microenvironmental cues, we characterized GC cytokine effects on EBV latency protein expression and on the EBV epigenome. We confirmed and extended prior studies highlighting GC cytokine effects in support of the latency II transition. The T-follicular helper cytokine interleukin 21 (IL-21), which is a major regulator of GC responses, and to a lesser extent IL-4 and IL-10, hyper-induced LMP1 expression, while repressing EBNA expression. However, follicular dendritic cell cytokines including IL-15 and IL-27 downmodulate EBNA but not LMP1 expression. CRISPR editing highlighted that STAT3 and STAT5 were necessary for cytokine mediated EBNA silencing via epigenetic effects at the EBV genomic C promoter. By contrast, STAT3 was instead necessary for LMP1 promoter epigenetic remodeling, including gain of activating histone chromatin marks and loss of repressive polycomb repressive complex silencing marks. Thus, EBV has evolved to coopt STAT signaling to oppositely regulate the epigenetic status of key viral genomic promoters in response to GC cytokine cues.

JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines.

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.