Interleukin-1 Receptor Research Articles

H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells.

H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells.

Interleukin-6 in neuroimmunological disorders: Pathophysiology and therapeutic advances with satralizumab.

Interleukin-6 in neuroimmunological disorders: Pathophysiology and therapeutic advances with satralizumab.

An engineered Treg selective immunocytokine induces sustained immune modulation in a preclinical model of hemophilia A.

An engineered Treg selective immunocytokine induces sustained immune modulation in a preclinical model of hemophilia A.

Trial in progress: A first-in-human (FIH) phase I study of PTX-912 in patients with locally advanced or metastatic solid tumors.

TPS2694 Background: High-dose IL-2 (HD IL-2) received FDA approval for metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC), but its use is limited by severe systemic toxicities. While PD-1 blockade has improved overall survival in 20–30% of cancer patients, resistance remains a significant challenge. Notably, HD IL-2 has shown durable anti-tumor effects in mM and mRCC patients who have progressed on anti-PD-1 therapy. Moreover, combining IL-2 with pembrolizumab in mRCC demonstrated a durable response rate of 70%, compared to objective response rates (ORR) of 20% and 33% with IL-2 and pembrolizumab monotherapy, respectively ( Chatzkel et al., Clin Genitourin Cancer(2022)) . These findings suggest that combining IL-2 receptor (IL-2R) activation with PD-1 blockade may be a promising strategy to overcome PD-1 resistance and enhance clinical outcomes. PTX-912 is a novel, first-in-class bifunctional PD-1-proIL-2v fusion protein designed to synergize PD-1 blockade with PD-1-cis-directed IL-2R agonism specifically within the tumor microenvironment (TME), reducing systemic toxicities typically associated with high dose IL-2 therapy. Methods: This first-in-human (FIH), multi-center Phase I study (NCT06190886) evaluates the safety, tolerability, and preliminary efficacy of PTX-912 in patients with locally advanced or metastatic solid tumors who have had disease progression on all available standard of care and/or refused available standard of care therapies that would confer clinical benefit. Eligible patients must have measurable disease per RECIST v1.1 and may have received any number of prior therapies. Key exclusions include immunodeficiency, unresolved toxicities > Grade 1 per NCI CTCAE from prior therapy, active autoimmune disease, primary CNS or leptomeningeal involvement, history of transplant, recent major surgery, and significant cardiac or pulmonary dysfunction. The study includes dose escalation (Part 1a) and dose expansion (Part 1b) cohorts. In Part 1a, seven dose levels (DL1–7) will be tested, with DL1–3 following an accelerated titration design and DL4–7 using a standard 3+3 design. The primary objectives are to determine the maximum tolerated dose (MTD), optimal biological dose (OBD), and/or the recommended Phase II dose (RP2D) of PTX-912, assessed via dose-limiting toxicities (DLTs). Patients with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), or other populations identified based on Part 1a data will be enrolled in Part 1b. In Part 1a, patients will receive intravenous infusions of PTX-912 every two weeks (Q2W), followed by subsequent cycles with a 28-day DLT observation period. Study enrollment began in June 2024 in the United States at 3 centers. Cohorts 1 to 4 (6 patients) have been completed without DLT. Enrollment to cohort 5 is currently ongoing. Clinical trial information: NCT06190886 .

How variants in inflammatory mediator genes influence symptom severity of psychiatric disorders: Findings from the PsyCourse study.

How variants in inflammatory mediator genes influence symptom severity of psychiatric disorders: Findings from the PsyCourse study.

Effect of spesolimab on sustained disease control in patients with generalized pustular psoriasis: Post hoc analysis of the EFFISAYIL 2 study.

Generalized pustular psoriasis (GPP) is a chronic inflammatory disease with an unpredictable disease course. Long-term treatment goals include sustained resolution of skin symptoms, prevention of new flares, and improvement in quality of life (QoL). To compare the effect of the interleukin-36 receptor monoclonal antibody spesolimab 600mg subcutaneous (SC) loading dose (LD) followed by 300mg SC every 4weeks (q4w) versus placebo on skin symptoms and QoL burden in patients with GPP. A post hoc analysis of the EFFISAYIL 2 trial (NCT04399837) was conducted to assess the proportion of patients with sustained improvement of skin symptoms (GPP Physician Global Assessment total score, 0 or 1) and QoL burden (Dermatology Life Quality Index score, 0 or 1) at all visits up to week 48. Among the patients who received spesolimab 600mg SC LD followed by 300mg SC q4w, 63.3% had sustained improvement of skin symptoms (vs 29.0%; placebo), and 24.1% had sustained improvement of QoL burden (vs 3.2%; placebo). Retrospective, descriptive, post hoc analysis. Spesolimab 600mg SC LD followed by 300mg SC q4w provides sustained improvement of skin symptoms and QoL burden in a substantially higher proportion of patients with GPP versus placebo.

Analysis of genetic mutation profile and CNS pharmacokinetics in relapsed/refractory primary CNS lymphoma patients responding to novel emavusertib (IRAK4i) and BTKi combination.

2085 Background: Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma with no approved treatments for relapsed/refractory (R/R) patients, representing a critical unmet need. MyD88 mutations in ~70% of PCNSL patients drive Interleukin-1 receptor associated kinase 4 (IRAK4) activation, promoting NF-κB signaling, inflammation, and tumor progression. Emavusertib, a potent oral IRAK4 inhibitor, crosses the blood-brain barrier and shows preclinical synergy with Bruton tyrosine kinase inhibitors (BTKi), re-sensitizing BTKi-resistant cell lines. This study evaluates the molecular and pharmacokinetic (PK) data associated with responses to emavusertib + ibrutinib combination therapy in R/R PCNSL patients. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). Pre-dose and 1.5-hour post-dose plasma samples were collected on Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1. Cerebrospinal fluid (CSF) samples were obtained via a lumbar puncture within 1.5 hrs of collection of the post-dose plasma PK sample on Cycle 3 Day 1. Mutation analysis was based on patients’ molecular pathology reports provided by trial sites. Sequencing of archival tissues, CSF and plasma are in progress. Results: As of 06 December 2024, CSF concentration data were available for 7 PCNSL patients. The mean emavusertib concentration in CSF was 81.3 ng/ml (54.7-104.0) in patients receiving 100 mg emavusertib BID (n = 4). In patients receiving 200 mg emavusertib BID (n = 3), the mean emavusertib concentration in CSF was higher at 175.7 ng/ml (114.8-209.4), which is 2.2X the mean value in patients who received 100 mg emavusertib BID (p-value = 0.02). All 7 patients received 560 mg ibrutinib QD, and the ibrutinib concentrations in the CSF were consistent with findings from previously published clinical studies. MyD88 mutation status was available for 7 patients of which all had prior exposure to BTKi regimens. Among these, 6 patients had MyD88 mutation of which 4 patients had responded (3 complete responses and 1 partial response) to emavusertib + ibrutinib combination with duration of response (DOR) up to 18.9 months with data collection ongoing. Conclusions: Preliminary CNS pharmacokinetic data demonstrates that emavusertib concentration in CSF increases with increasing emavusertib dose. Patients with MyD88 mutations showed expected promising preliminary efficacy to emavusertib + ibrutinib combination and may overcome BTKi resistance. Enrollment in this trial is ongoing. Clinical trial information: NCT03328078 .

Resveratrol exerts antiviral activity against pseudorabies virus through regulation of the OPN-ERK/JNK-IL-1β signaling axis.

Resveratrol exerts antiviral activity against pseudorabies virus through regulation of the OPN-ERK/JNK-IL-1β signaling axis.

Deficiency of the interleukin-1 receptor antagonist: Characterizing the molecular consequences of loss-of-function IL1RN variants from structural and biochemical evidence

Deficiency of the interleukin-1 receptor antagonist: Characterizing the molecular consequences of loss-of-function IL1RN variants from structural and biochemical evidence

Inhibition of interleukin-1 signaling protects against Group B streptococcus-induced preterm birth and fetal loss in mice.

Group B streptococcus is a common microbial agent associated with spontaneous preterm birth and fetal inflammatory response syndrome. In this study, we evaluated the utility of rytvela, a novel peptide antagonist of the interleukin-1 receptor, to suppress inflammatory activation, prolong gestation and improve neonatal outcomes induced in mice by Group B streptococcus. Pregnant mice were administered rytvela or PBS on gestation day 16.5, immediately prior and following surgical administration of heat-killed Group B streptococcus (hkGBS) or PBS into the uterine cavity. Treatment with rytvela prevented preterm delivery and alleviated fetal demise in utero and in the perinatal phase elicited by hkGBS. Compared to pups exposed to hkGBS alone, pups of dams co-administered rytvela exhibited substantially improved survival and growth through to weaning. Analysis by qPCR showed expression of inflammatory cytokine genes Il1b, Il6, Tnf, and Ifng in uterine tissues, and Il1b, Il6, and Tnf in fetal membranes, were stimulated by hkGBS and this increase was suppressed by co-administration of rytvela. Premature induction of uterine activation gene Ptgs2 in the myometrium was also attenuated by rytvela treatment. These data show that activation of IL1-mediated signaling in response to Group B streptococcus triggers an inflammatory cascade that causes preterm parturition and fetal inflammatory injury, and that rytvela can suppress inflammatory mediators to substantially improve pregnancy and fetal outcomes. Our findings add to accumulating evidence supporting clinical investigation of rytvela for fetal protection and delaying preterm birth.

The IRAK4 long isoform as widely upregulated in non-splicesome mutated acute myeloid leukemia and as altered by hypomethylating agent therapy.

6524 Background: IRAK4, a kinase effector of MyD88 signaling downstream of Toll-Like Receptor and IL-1 receptor pathways, has recently been shown to function independently of MyD88 in Myelodysplastic Syndrome (MDS) and AML leukemic cells. Our previous research demonstrated that AML leukemic stem and progenitor cells (LSPC) rely on signaling through IRAK4. Notably, AML LSPCs express a hypermorphic long splice isoform of IRAK4 (IRAK4-L) resulting from the inclusion of exon 4. IRAK4 inhibitors, currently in clinical trials for the treatment of MDS and AML, show improved efficacy in spliceosome mutants, which preferentially express IRAK4-L. However, in patients without known spliceosome mutations, the extent of IRAK4-L expression remains unclear. Additionally, the impact of IRAK4-L levels in Venetoclax and Azacitidine treatment is unknown in refractory or unfit AML. Methods: Umbilical cord vein blood stem cells expressing MLL-AF9 and NRAS G12D (CD34+MA9.NRAS) were maintained in vitro using supplemented media. Venetoclax and Azacitidine doses were incrementally increased in combination until cells tolerated co-treatment with up to 1 µM of each compound with minimal cell death. Patient-derived xenograft (PDX) samples were obtained from the Cincinnati Children’s Biobank and included AML samples from diverse genetic backgrounds, relapsed/refractory cases, and pediatric populations (ages 1-20). Cell lysates were normalized to total protein and analyzed using a chemiluminescent capillary-based immunoblotting system, which requires minimal lysate quantities. An IRAK4 C-terminus antibody was used to detect both the shorter and longer IRAK4 protein isoform. RNA sequencing was performed, and transcripts were normalized per million counts. IRAK4 transcript ratios were calculated by dividing the total long isoform transcripts by the short isoform transcript for each condition in duplicate. Results: Analysis of PDX and human AML cell lines revealed that 8/9 PDX preferentially expressed the IRAK4-L isoform (>70% of IRAK4-L), with 4/9 PDX samples and 5/6 previously uncharacterized cell lines producing it almost exclusively (>95% IRAK4-L). MA9.NRAS cells predominantly express IRAK4-L, but transiently shifted to IRAK4-S during treatment with AZA/VEN (27% IRAK4-S), an effect reversed upon recovery from treatment. Conclusions: IRAK4-L is widely expressed in AML patient-derived samples, including those with complex karyotypes and TP53 mutations, suggesting that IRAK4 inhibitors may be useful beyond splicing factor-mutant MDS/AML. Our models demonstrate that changes in IRAK4-L expression during treatment with hypomethylating agents may be useful as a biomarker to guide therapy strategies. Further research is needed to understand how prolonged treatment and other standard of care therapies affect IRAK4-L expression and sensitivity to IRAK4 inhibitors.

CD123 expression and its correlation with mutation profile in acute myeloid leukemia.

e18524 Background: CD123, the interleukin-3 receptor α-chain, is frequently overexpressed by acute myeloid leukemia (AML) blasts and may represent a potential target for chemo-immunotherapy. Methods: We retrospectively studied consecutive patients (pts) with AML to assess CD123 expression by blasts, its correlation with the 2022 World Health Organization (WHO-5) and International Consensus Classification (ICC), and related mutational profiles. Results: 99 pts were included, with a median age of 66 yrs (range, 26–90). 59% had newly diagnosed (ND) AML, 24% had relapse/refractory (RR) AML, 12% had secondary AML (S-AML), and 5% had therapy-related AML (t-AML). The median percentage of blasts expressing CD123 was 85% (range, 13–100), with 57 pts (58%) having ≥80% expression. The median CD123 fluorescence intensity (MFI) was 1189 (interquartile range (IQR), 606–2235). The median percentage of blasts expressing CD123 was 84% (range, 14–99) in ND AML, 87% (range, 61–100) in RR AML, and 82% (range, 13–99) in S-AML and t-AML, with median CD123-MFI 1216 (IQR, 581–2058), 1128 (IQR, 803–2008), and 1006 (IQR, 391–3482), respectively. Age (66 vs. 67 yrs), blast percentage (40% vs. 53%), median LDH (380 vs. 294), and adverse karyotype (64% vs. 53%) were similar between pts with <80% and >80% CD123 expression. The most frequent AML categories for ND AML, based on the WHO-5 and ICC classifications, are shown in the Table. 5 pts with acute erythroid leukemia, as per WHO-5, were classified as TP53 mutated by ICC and had a median CD123 expression of 32% (range, 13-37). The most common mutations in the entire cohort were TP53 (32%), DNMT3A (20%), RUNX1 (18%), TET2 (16%), FLT3 -ITD (10%), NRAS (10%), U2AF1 (10%), IDH1 (10%), SRSF2 (10%), and NPM1 (9%). FLT3 -ITD was more common in pts with CD123 expression ≥80% (16% vs. 2%, p=0.04), whereas NRAS was more frequent in those with CD123 <80% (19% vs. 4%, p=0.02). Trends showed higher frequencies of TP53 (38% vs. 28%), SRSF2 (14% vs. 7%), and ASXL1 (12% vs. 5%) in pts with CD123 <80%. RUNX1 (21% vs. 14%) tended to be more common in those with CD123 ≥80%. Similar trends were seen using the third quartile CD123-MFI cutoff, although the difference in NRAS was not statistically significant. Conclusions: CD123 expression is consistent across AML subtypes; shows a positive correlation with FLT3 -ITD, a negative correlation with NRAS , and a trend towards TP53 , suggesting potential predictive markers for anti-CD123 therapy response. Genes (entire cohort) CD123 <80%n=42 (%) CD123 ≥80%n=57 (%) p-value Classification (ND AML) CD123 <80%n=25 (%) CD123 ≥80%n=33 (%) p-value TP53 16 (38) 16 (28) 0.3 WHO 0.9 DMT3A 7 (17) 13 (23) 0.5 Myelodysplasia-related (MR) 12 (48) 17 (52) RUNX1 6 (14) 12 (21) 0.4 Defined by differentiation 5 (20) 4 (12) TET2 8 (19) 8 (14) 0.5 NPM1 3 (12) 6 (18) FLT3-ITD 1 (2) 9 (16) 0.04 ICC 0.4 NRAS 8 (19) 2 (4) 0.02 TP53 mutated 8 (32) 5 (15) U2AF1 4 (10) 6 (11) 1.0 MR 7 (28) 13 (39) IDH1 3 (7) 7 (12) 0.5 NPM1 3 (12) 6 (18) SRSF2 6 (14) 4 (7) 0.3 NOS 2 (8) 3 (9)

Implication of serum soluble IL-2 receptor α in type 2 diabetes mellitus.

The aim of this study was to determine the association of serum soluble IL-2 receptor α (sIL-2RA) with T2DM-related characteristics and complications. Serum sIL-2RA levels were determined in 156 T2DM patients, and the association with T2DM-related characteristics and complications was evaluated. Serum sIL-2RA levels were significantly increased in T2DM patients with diabetic kidney disease (DKD) (median, IQR, 1434.9, 958.1-1896.0, pg/ml), in comparison with those without DKD (median, IQR, 851.2, 660.2-1089.9, pg/ml)(P < 0.001). The ROC analysis revealed good performance of sIL-2RA for identifying DKD, with the areas under the curve of 0.789 (95%CI of 0.711-0.867, P < 0.001). The correlation analyses showed significantly positive correlations of serum sIL-2RA with urea (r = 0.458, P < 0.001), creatinine (r = 0.508, P < 0.001) and uACR (r = 0.469, P < 0.001), and negative correlation with eGFR (r=-0.561, P < 0.001). The multivariate analyses showed that serum sIL-2RA was independently associated with the increased risks of DKD (OR, 95%CI, 6.539, 1.401-30.529, P = 0.017) and DR (OR, 95%CI, 3.606, 1.073-12.114, P = 0.038). Additionally, serum sIL-2RA was significantly associated with inflammatory indicators in DKD patients, and with metablic indicators in non-DKD patients (all P < 0.05). Serum sIL-2RA may be closely associated with inflammation, glucose and lipid metabolisms, DKD and DR risks in T2DM. Furthermore, it may be a potential biomarker for T2DM-related micro-vascular complications.

Mendelian randomization reveals causal relationships between cytokines and male reproductive diseases.

Mendelian randomization reveals causal relationships between cytokines and male reproductive diseases.

Effectiveness of satralizumab in a real-world clinical setting in Japan: Interleukin-6 receptor inhibition in neuromyelitis optica spectrum disorder: A six-month interim analysis of a multicenter medical chart review.

Effectiveness of satralizumab in a real-world clinical setting in Japan: Interleukin-6 receptor inhibition in neuromyelitis optica spectrum disorder: A six-month interim analysis of a multicenter medical chart review.

A phase 1b study of combined treatment with dupilumab (anti-IL-4Ra) and cemiplimab (anti-PD-1) in patients with early-stage, resectable NSCLC.

TPS2696 Background: For resectable stage II/III non-small cell lung cancer (NSCLC), neoadjuvant chemoimmunotherapy has become standard of care. Patients with Stage I disease (as per AJCC 8) were excluded from chemoimmunotherapy studies given prior data demonstrating no survival benefit from perioperative chemotherapy. However, even patients with Stage 1A (&lt; 2cm) tumors have a 30% chance of recurrence (Altorki et al, NEJM 2023). Recent research has revealed that tumor-infiltrating myeloid cells express an IL-4 responsive transcriptional signature, and IL-4 signaling within monocyte-derived macrophages plays an essential role in NSCLC progression and tumor microenvironment remodeling. Dupilumab, a monoclonal antibody targeting IL-4 receptor alpha (IL-4Rα), is currently approved for treating asthma and allergic rhinitis, and preclinical studies have demonstrated that blocking IL-4 signaling can significantly reduce lung tumor burden by activating dendritic cells and effector T cells to generate a robust immune response against tumor antigens. These findings are supported by early clinical evidence from a phase 1/2 trial showing that dupilumab can work synergistically with PD-(L)1 inhibition to induce sustained tumor responses in some patients with metastatic NSCLC who had previously progressed on immunotherapy. Whether similar synergy would be seen in the pre-operative setting in patients with Stage 1 tumors, or patients not suitable for chemoimmunotherapy, is not known, though an immunotherapy-alone approach may enable much more brief pre-operative treatment given that T cell changes peak at one week in the metastatic setting, and prior studies show PD-1 blockade alone can cause robust responses in some patients within only a few weeks. Methods: This Phase 1b/2a single-arm trial will enroll patients with early-stage (&gt; T1b), resectable NSCLC. Patients will receive one dose each of dupilumab (600mg SC) and cemiplimab (350mg IV) on day 1, followed by surgical resection within 15-21 days, with delays beyond 8 weeks considered a delay of surgery. The trial consists of a 3+3 safety run-in (Phase 1b, up to 6 patients) followed by a Simon's two-stage expansion (Phase 2a, up to 24 total patients). The primary endpoints are safety/feasibility (Phase 1b) and major pathological response rate, defined as ≤10% viable tumor at resection (Phase 2a). Secondary endpoints include time to surgery, pathological complete response rate, event-free survival, and overall survival. Comprehensive correlative studies will characterize the immune response through serial blood sampling (days 1, 4, 8, 15, surgery, and 30 days post-op), matched proteomic and transcriptomic tumor tissue analysis (pre-treatment and operative samples), and stool microbiome profiling to identify potential biomarkers of response. Clinical trial information: NCT06088771 .

Long-term functional prognosis with tocilizumab in severe COVID-19 infection: A multicenter prospective observational study on mechanically ventilated ICU patients in the COVID-19 recovery study II.

Long-term functional prognosis with tocilizumab in severe COVID-19 infection: A multicenter prospective observational study on mechanically ventilated ICU patients in the COVID-19 recovery study II.

Dissecting the causal effects of interleukin receptor-related factors and the risk of developing endometriosis: a two-sample Mendelian randomization study

This study investigates the causal associations between interleukin receptor-related factors and the development of endometriosis, as their etiology and pathophysiology remain largely unknown. A two-sample Mendelian randomization (MR) approach was employed to analyze genetic variants associated with interleukin receptor related factors as instrumental variables (IVs). The F-values have to be > 10 to exclude weak instrumental bias. The primary analysis was conducted using the inverse variance weighted (IVW) method, with confirmation using the MR-Egger, weighted median (WM), simple mode, and weighted mode methods. Sensitivity analyses were performed to ensure robustness, including tests for heterogeneity, pleiotropy, and leave-one-out. Multivariable MR (MVMR) analysis was used to assess the direct and mediated effects of immune cells. The results indicated significant causal associations between interleukin receptor factors prot-a-1542 (IL-6Rβ), prot-a-1530 (IL-3Rα), and prot-b-38 (IL-1RL1) and endometriosis. Reverse MR analysis showed that endometriosis did not significantly affect prot-a-1530 or prot-b-38. After adjusting for confounders like body mass index and smoking, these factors retained their significance. Additionally, immune cells(ebi-a-GCST90001951) were found to mediate the relationship between prot-b-38 and endometriosis, with an indirect effect accounting for approximately 6.38% of the total effect. This study provides new insights into endometriosis mechanisms involving specific interleukin receptor factors.

The effect of probiotic bacteria and pharmacological anti-inflammatory effects on the size of myocardial infarction in rats with systemic inflammation

BACKGROUND: In recent years, it has been shown that certain probiotics have a cardioprotective effect in conditions of comorbidity and systemic inflammation. The mechanisms of probiotic-mediated cardioprotection have not been studied in practice. There is an assumption that the heart attack-limiting effect of probiotics is mediated by their anti-inflammatory effect. AIM: To study the severity of the cardioprotective effect of a mixture of probiotic strains of Lactobacillus acidophilus (LA-5) and Bifidobacterium animalis subsp. lactis (BB-12) in rats with systemic inflammatory response syndrome in comparison with the use of IL-1 receptor blockers, AT1 angiotensin II receptors, M-cholinergic receptors, as well as an inhibitor of tumor necrosis factor alfa binding to its receptors. METHODS: The experiments were performed on male Wistar stock rats on a model of systemic inflammatory response syndrome. The rats of the corresponding groups, after chemical induction of a systemic inflammatory response, were intragastrically injected with probiotic strains, losartan and hyoscine butyl bromide; subcutaneously — etanercept and anakinra for 8 days. The assessment of myocardial resistance to ischemic-reperfusion injury was carried out on the model of global ischemia-reperfusion of an isolated heart at an upgraded Langendorff facility, by planimetric estimation of the size of the necrosis zone. The concentration of cytokines in blood plasma was assessed by enzyme immunoassay. RESULTS: The size of the myocardial necrosis zone in the systemic inflammatory response group, rats with systemic inflammatory response syndrome, was significantly higher than in the control group — 45% (38; 48)% and 30% (26; 31)% (p 0.05). In the groups of probiotic strains, anakinra and losartan, the size of the necrosis zone was 32% (28; 35)%, 26% (24; 35)% and 30% (25; 36)%, which is less than in the systemic inflammatory response group (p 0.05). In the etanercept and hyoscine butyl bromide groups, the size of the necrosis zone was 35% (26; 36)% and 42% (32; 46)%, not significantly different from the SIR group (p 0.05). Hemodynamic parameters of the isolated heart did not differ between the groups. In the systemic inflammatory response group, the concentration of proinflammatory cytokines and transforming growth factor beta in blood plasma was significantly higher than in the control group. At the same time, in the groups of probiotic strains, anakinra, losartan and hyoscine butyl bromide, a significant decrease in the levels of certain cytokines was noted, confirming the presence of an anti-inflammatory effect. CONCLUSION: The introduction of probiotics to rats with systemic inflammatory response syndrome caused a decrease in the size of the necrosis zone. At the same time, the blockade of tumor necrosis factor alfa binding to receptors and the blockade of M-cholinergic receptors were not accompanied by a decrease in size of the necrosis zone in this model. Pharmacological blockade of the IL-1 and AT1 angiotensin II receptors had a cardioprotective and anti-inflammatory effect similar to the probiotic strains group, which indicates the unidirectional effect of the tested effects.

A critical role for IL-21/IL-21 receptor signaling in isoproterenol-induced cardiac remodeling

Increased cytokine secretion from immune cells is often associated with cardiac remodeling and heart failure due to pressure overload. Several reports suggest that the IL-21/IL-21 receptor (IL-21R) signaling pathway may play a critical role in heart failure progression, but the exact mechanism remains unclear. In this study, isoproterenol (ISO) was used to induce heart failure in mice and found that ISO injection caused significant upregulation of IL-21 and the IL-21R in the heart of mice. Subsequently, IL-21 receptor-deficient (IL-21R−/−) mice were used to evaluate the cardioprotective effects of IL-21/IL-21R. Importantly, we found a significant reduction in myocardial hypertrophy, inflammation, and apoptosis in ISO-treated IL-21R−/− mice compared to WT mice. Furthermore, the frequency of CD4+IFN-γ+ cells was significantly reduced in ISO-treated IL-21R−/− mice. Co-culture studies showed that the adhesion rate of CD4+ T cells isolated from IL-21R−/− to cardiac fibroblasts was significantly reduced compared to co-cultures isolated from WT mice. Accordingly, significant downregulation of α-SMA was detected in cardiac fibroblasts when cocultured with CD4+ T cells isolated from IL-21R−/− mice. Furthermore, IL-21 could directly induce cardiomyocyte hypertrophy and apoptosis and exacerbate ISO-induced myocardial damage through activation of STAT3 signaling pathway. Our study demonstrates the mechanism of IL-21 and its receptor in the progression of myocardial hypertrophy and fibrosis and highlights that the absence of IL-21R may provide protection against myocardial damage, thus providing a new potential therapeutic target for the treatment of heart failure.