Mesenchymal stromal cells protect tissues from Th1 immune responses via IL-11 secretion.

Mesenchymal stromal cells (MSCs) have been shown to modulate the function of various subsets of T cells such as naïve CD4+ T cells and IFNγ+CD4+ Th1 cells; however, mechanisms underlying this regulation have not been fully deciphered. Our in vitro culture assays demonstrate that MSCs suppress the activation and function of CD4+ T cells by secreting interleukin 11, and neutralization of IL11 abrogates MSC-mediated suppression of CD4+ T cell function. Moreover, delayed-type, exogenous supplementation of IL11 significantly suppressed IFNγ+ expression by Th1 cells. Th1 and CD8+ cells play central roles in T cell-mediated tissue damage. Using a murine model of hypersensitivity response to study T cell-mediated tissue damage, we show that silencing IL11 in MSCs significantly abates the capacity of MSCs to suppress the generation of IFNγ-secreting CD4+ and CD8+ cells, failing to prevent T cell-mediated tissue inflammation and tissue damage.

Chronic Kidney Disease Diets for Kidney Failure Prevention: Insights from the IL-11 Paradigm.

Nearly every fifth adult in the United States and many older adults worldwide are affected by chronic kidney disease (CKD), which can progress to kidney failure requiring invasive kidney replacement therapy. In this review, we briefly examine the pathophysiology of CKD and discuss emerging mechanisms involving the physiological resolution of kidney injury by transforming growth factor beta 1 (TGFß1) and interleukin-11 (IL-11), as well as the pathological consequences of IL-11 overproduction, which misguides repair processes, ultimately culminating in CKD. Taking these mechanisms into account, we offer an overview of the efficacy of plant-dominant dietary patterns in preventing and managing CKD, while also addressing their limitations in terms of restoring kidney function or preventing kidney failure. In conclusion, this paper outlines novel regeneration strategies aimed at developing a reno-regenerative diet to inhibit IL-11 and promote repair mechanisms in kidneys affected by CKD.

Pharmacokinetic and Metabolomic Studies with a Promising Radiation Countermeasure, BBT-059 (PEGylated interleukin-11), in Rhesus Nonhuman Primates.

BBT-059, a long-acting PEGylated interleukin-11 (IL-11) analog that is believed to have hematopoietic promoting and anti-apoptotic properties, is being developed as a potential radiation medical countermeasure (MCM) for hematopoietic acute radiation syndrome (H-ARS). This agent has been shown to improve survival in lethally irradiated mice. To further evaluate the drug's toxicity and safety profile, 12 naïve nonhuman primates (NHPs, rhesus macaques) were administered one of three doses of BBT-059 subcutaneously and were monitored for the next 21 days. Blood samples were collected throughout the study to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug as well as its effects on complete blood counts, cytokines, vital signs, and to conduct metabolomic studies. No adverse effects were detected in any treatment group during the study. Short-term changes in metabolomic profiles were present in all groups treated with BBT-059 beginning immediately after drug administration and reverting to near normal levels by the end of the study period. Several pathways and metabolites, particularly those related to inflammation and steroid hormone biosynthesis, were activated by BBT-059 administration. Taken together, these observations suggest that BBT-059 has a good safety profile for further development as a radiation MCM for regulatory approval for human use.

Brain Metastasis from EGFR-Mutated Non-Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up-Regulates PDL1 and Promotes Immune Escape.

Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8+ T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.

Targeting IL-11 to reduce fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension-associated lung fibrosis.

BACKGROUND AND PURPOSE: IL-11 is a member of the IL-6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL-11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow-derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL-11 on fibrocytes is unknown. We investigated the role of IL-11 system on fibrocyte activation in different in vitro and in vivo models of lung fibrosis associated with pulmonary hypertension. EXPERIMENTAL APPROACH: Human fibrocytes were isolated from peripheral blood of six healthy donors. Recombinant human (rh)-IL-11 and soluble rh-IL-11 receptor, α subunit (IL-11Rα) were used to stimulated fibrocytes in vitro to measure:- cell migration in a chemotactic migration chamber, fibrocyte to endothelial cell adhesion in a microscope-flow chamber and fibrocyte to myofibroblast transition. Mouse lung fibrosis and pulmonary hypertension was induced using either IL-11 (s.c.) or bleomycin (intra-tracheal), while in the rat monocrotaline (intra-tracheal) was used. In vivo siRNA-IL-11 was administered to suppress IL-11 in vivo. KEY RESULTS: RhIL-11 and soluble rhIL-11Rα promote fibrocyte migration, endothelial cell adhesion and myofibroblast transition. Subcutaneous (s.c.) IL-11 infusion elevates blood, bronchoalveolar and lung tissue fibrocytes. SiRNA-IL-11 transfection in bleomycin and monocrotaline animal models reduces blood and lung tissue fibrocytes and reduces serum CXCL12 and CXCL12/CXCR4 lung expression. CONCLUSION AND IMPLICATIONS: Targeting IL-11 reduces fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension-associated lung fibrosis.

Pirfenidone and nintedanib attenuates pulmonary artery endothelial and smooth muscle cells transformations induced by IL-11.

Idiopathic pulmonary fibrosis (IPF) associated to pulmonary hypertension (PH) portends a poor prognosis, characterized by lung parenchyma fibrosis and pulmonary artery remodeling. Serum and parenchyma levels of Interleukin 11 (IL-11) are elevated in IPF-PH patients and contributes to pulmonary artery remodeling and PH. However, the effect of current approved therapies against IPF in pulmonary artery remodeling induced by IL-11 is unknown. The aim of this study is to analyze the effects of nintedanib and pirfenidone on pulmonary artery endothelial and smooth muscle cell remodeling induced by IL-11 in vitro. Our results show that nintedanib (NTD) and pirfenidone (PFD) ameliorates endothelial to mesenchymal transition (EnMT), pulmonary artery smooth muscle cell to myofibroblast-like transformation and pulmonary remodeling in precision lung cut slices. This study provided also evidence of the inhibitory effect of PFD and NTD on IL-11-induced endothelial and muscle cells proliferation and senescence. The inhibitory effect of these drugs on monocyte arrest and angiogenesis was also studied. Finally, we observed that IL-11 induced canonical signal transducer and activator of transcription 3 (STAT3) and non-canonical mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation, but, PFD and NTD only inhibited ERK1/2 phosphorylation. Therefore, this study provided evidence of the inhibitory effect of NTD and PFD on markers of pulmonary artery remodeling induced by IL-11.

Serum levels of IL-9 and IL-11 serve as predictors for the occurrence of early neurologic deterioration in patients with cerebral infarction.

BACKGROUND AND AIM: Early neurological deterioration (END) is a common complication of cerebral infarction and a significant contributor to poor prognosis. Our study aimed to investigate the predictive value of interleukin-9 (IL-9) and interleukin-11 (IL-11) in relation to the occurrence of END in patients with cerebral infarction. MATERIALS AND METHODS: 102 patients with cerebral infarction and 64 healthy controls were collected. Patients were categorized into two groups based on the development of END following admission: the END group (n = 44) and the non-END group (n = 58). Enzyme-linked immunosorbent assay was used to determine the serum levels of IL-9, IL-11, and BDNF. RESULTS: Serum IL-9 was higher and IL-11 lower in the END group than those in the non-END group (P < 0.01). IL-9 correlated positively with NIHSS score (r = 0.627) and infarction volume (r = 0.686), while IL-11 correlated negatively (r = -0.613, -0.679, respectively). Logistic regression identified age, NIHSS score, and IL-9 as risk factors (P < 0.01), and IL-11 as protective (P < 0.01). Combined IL-9 and IL-11 had an ROC curve area of 0.849. BDNF correlated negatively with IL-9 (r = -0.703) and positively with IL-11 (r = 0.711). CONCLUSION: Serum IL-9 and IL-11 levels can predict the occurrence of END in patient with cerebral infarction and are correlated with serum BDNF levels.

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer.

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

A real-world observation on thrombopoietic agents for patients with cancer treatment-induced thrombocytopenia in China: A multicenter, cross-sectional study.

BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.

IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFß.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFß. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFß signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFß at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFß-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

[Effect of recombinant human thrombopoietin on platelets in rats with D-galactosamine salt-induced acute liver failure].

OBJECTIVE: To evaluate the effects of recombinant human thrombopoietin (rhTPO) on platelet count (PLT) and liver function in acute liver failure (ALF) rats by observing the dynamic changes of PLT, thrombopoietin (TPO) and liver function during ALF. METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into model group, TPO group and interleukin-11 (IL-11) group using a random number table method, with eight rats in each group. All rats were intraperitoneally injected with D-galactosamine (D-GalN, 1 500 mg/kg, dosed within 72 hours) to induce the ALF model. After modeling, rats in TPO group was received subcutaneous injection of 15 µg/kg of rhTPO for 5 days, and rats in IL-11 group was received subcutaneous injection of 0.45 mg/kg of IL-11 for 5 days. Venous blood samples were collected before and at 1, 3, 5, 7 and 12 days after molding for whole blood cell detection. The level of TPO in serum was detected by enzyme-linked immunosorbent assay (ELISA). Liver function indexes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (ALB) were measured before and at 1, 3 and 5 days after modeling. The rats were sacrificed 12 days after the modeling, and the pathological changes of liver tissue were observed by hematoxylin-eosin (HE) staining. RESULTS: Two rats in each group died within 24-48 hours after modeling. HE staining showed that all three groups of ALF rats showed large flake necrosis of hepatocytes, disorder of hepatic lobular structure, mesh scaffold collapse, hepatic sinus congestion and hemorrhage, and flake infiltration of inflammatory cells on day 12 after modeling. The levels of serum ALT, AST and TBil of rats in each group were significantly increased 1 day after modeling and then decreased. The level of ALB decreased significantly on the first day after modeling and then increased, but there was no significant difference in the trend of liver function indexes among the three groups. PLT in the three groups decreased rapidly on day 1 after modeling, and then recovered gradually with the improvement of liver function. The PLT of the TPO group rose to the peak value 7 days after molding and was significantly higher than that of the model group [PLT (×109/L): 1 673.3±347.5 vs. 855.3±447.0, P < 0.05], while there was no significant difference between the IL-11 group and the model group [PLT (×109/L): 1 350.3±386.6 vs. 855.3±447.0, P > 0.05]. The level of serum TPO of the three groups increased significantly on day 1 after modeling, then decreased, and dropped to the lowest value on day 5, but there was no significant difference in the trend of serum TPO level among the three groups. CONCLUSIONS: PLT in ALF rats decreased rapidly in the early stage and recovered gradually with the improvement of liver function, and the serum TPO level increased first and then decreased. Injection of rhTPO can significantly increase PLT in ALF rats, but has no significant effect on liver function and survival rate.

Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency.

IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.

Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway.

BACKGROUND: Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. METHODS: Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. RESULTS: Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. CONCLUSION: Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.

Exploring the role of interleukin 11 in cancer progression, patient survival, and therapeutic insights.

BACKGROUND: The Interleukin (IL)-11 gene, which is one of the members of the cytokine family, has an oncogenic role in some cancers. The main goal of this study is to analyze IL-11 expression level in 14 prevalent cancers and highlights its role in patients' survival, drug resistance, and sensitivities. Also, an association of this gene with metastasis and inflammation pathways has been investigated. METHODS AND RESULTS: Using the cancer genome atlas (TCGA) data, the level of IL-11 expression and its role in prognosis and survival rate were evaluated in 13 common cancers. Then, confirming the obtained in-silico outcomes, the relative expression level of this gene in colorectal cancer (CRC) samples and their adjusted tissues were assayed by the RT-qPCR method. Furthermore, to examine the association between IL-11 expression and drug resistance and sensitivity, PharmacoGX data was applied. The co-expression network was used to recognize the pathways in which IL-11 was involved. The results from the TCGA dataset indicated that the expression level of IL-11 increased significantly in 13 prevalence cancers compared to the control groups. Interestingly, this enhanced expression level is associated with a high rate of mortality in patients with bladder, stomach, colorectal, and endometrial cancers. Also, the co-expression network analysis showed a strong correlation between IL-11 and the genes of metastasis pathway and the genes related to the inflammation process. Finally, regarding drug sensitivity, IL-11 expression level can be introduced as a remarkable biomarker for cancer detection due to area under curve (AUC). CONCLUSION: Altered expression of the IL-11 gene is observed in 13 common cancers and is associated with prognosis and mortality rate in patients. Moreover, this gene can be considered a prognostic biomarker in different types of cancer, such as CRC.

NLRP1 restricts porcine deltacoronavirus infection via IL-11 inhibiting the phosphorylation of the ERK signaling pathway.

Continuously emerging highly pathogenic coronaviruses remain a major threat to human and animal health. Porcine deltacoronavirus (PDCoV) is a newly emerging enterotropic swine coronavirus that causes large-scale outbreaks of severe diarrhea disease in piglets. Unlike other porcine coronaviruses, PDCoV has a wide range of species tissue tropism, including primary human cells, which poses a significant risk of cross-species transmission. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) has a key role in linking host innate immunity to microbes and the regulation of inflammatory pathways. We now report a role for NLRP1 in the control of PDCoV infection. Overexpression of NLRP1 remarkably suppressed PDCoV infection, whereas knockout of NLRP1 led to a significant increase in PDCoV replication. A mechanistic study revealed that NLRP1 suppressed PDCoV replication in cells by upregulating IL-11 expression, which in turn inhibited the phosphorylation of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor U0126 effectively hindered PDCoV replication in pigs. Together, our results demonstrated that NLRP1 exerted an anti-PDCoV effect by IL-11-mediated inhibition of the phosphorylation of the ERK signaling pathway, providing a novel antiviral signal axis of NLRP1-IL-11-ERK. This study expands our understanding of the regulatory network of NLRP1 in the host defense against virus infection and provides a new insight into the treatment of coronaviruses and the development of corresponding drugs.IMPORTANCECoronavirus, which mainly infects gastrointestinal and respiratory epithelial cells in vivo, poses a huge threat to both humans and animals. Although porcine deltacoronavirus (PDCoV) is known to primarily cause fatal diarrhea in piglets, reports detected in plasma samples from Haitian children emphasize the potential risk of animal-to-human spillover. Finding effective therapeutics against coronaviruses is crucial for controlling viral infection. Nucleotide-binding oligomerization-like receptor (NLR) family pyrin domain-containing 1 (NLRP1), a key regulatory factor in the innate immune system, is highly expressed in epithelial cells and associated with the pathogenesis of viruses. We demonstrate here that NLRP1 inhibits the infection of the intestinal coronavirus PDCoV through IL-11-mediated phosphorylation inhibition of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor can control the infection of PDCoV in pigs. Our study emphasizes the importance of NLRP1 as an immune regulatory factor and may open up new avenues for the treatment of coronavirus infection.

Exploring the effect of LncRNA DANCR to regulate the Keap1-Nrf2/ARE pathway on oxidative stress in rheumatoid arthritis.

INTRODUCTION: Aberrant expression of long noncoding RNAs (LncRNAs) can regulate oxidative stress in rheumatoid arthritis (RA). This study focused on investigating the effects of LncRNA differentiation antagonizing nonprotein coding RNA (DANCR) regulation of Keap1-Nrf2/ARE pathway on inflammation and oxidative stress in RA. METHODS: The levels of LncRNA DANCR/miR-486-3p/Keap1 in peripheral blood of 30 RA groups and 30 normal subjects were examined, and the association of LncRNA DANCR with inflammatory indicators of RA was investigated. We stimulated fibroblast-like synoviocytes (FLS) from RA patients with tumor necrosis factor α and subsequently performed in vitro cellular assays to construct overexpression plasmids and small interfering RNAs of LncRNA DANCR to investigate the relationship between LncRNA DANCR and FLSs viability and migration in RA, as well as the effects on cellular oxidative stress factors and Keap1-Nrf2/ARE pathway; molecular biology analysis was used to predict microRNAs that can bind LncRNA DANCR, and luciferase verified the binding sites of LncRNA DANCR with Keap1 and miR-486-3p; to further refine the gene and protein expression results, we used reverse transcription-quantitative polymerase chain reaction and immunoblotting assays. RESULTS: In both groups of peripheral blood mononuclear cells, the expression levels of LncRNA DANCR and Keap1 messenger RNA were higher in the RA group than in the normal control group, and the opposite was true for miR-486-3p; LncRNA DANCR was positively correlated with total antioxidant capacity (TAOC), IL6, IL17, malondialdehyde (MDA), but not with IL11, rheumatoid factor, cyclic citrullinated peptide, superoxide dismutase (SOD), with 28-joint disease activity score, reactive oxygen species, C-reactive protein, and erythrocyte sedimentation rate were negatively correlated; overexpression of LncRNA DANCR stimulated the Keap1-Nrf2/ARE pathway, decreased the expression of IL10, SOD, TAOC, and increased the expression levels of MDA, IL11, IL-17, PD-L1, and silencing of LncRNA DANCR was the opposite, but knockdown of miR-486-3p or overexpression of keap1 reversed the expression of the above-mentioned inflammatory and oxidative factors. In addition, pcDNA-DANCR clearly showed stronger cell invasion and migration ability and exacerbated its inflammatory response, which may be related to the regulatory role of miR-486-3p and Keap1-Nrf2/ARE signaling pathway, and we verified their targeting relationship using dual luciferase, showing that DANCR could regulate Keap1-Nrf2/ARE through miR-486-3p modulates the Keap1-Nrf2/ARE pathway and affects inflammatory and oxidative responses in RA patients. CONCLUSION: The low-expressed LncRNA DANCR may regulate the Keap1-Nrf2/ARE pathway and suppress the inflammatory and oxidative responses in RA patients.

Interleukin-6 Family of Cytokines in Cancers.

Nine soluble ligands [interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine, interleukin-27 (IL-27), and interleukin-31] share the ubiquitously expressed transmembrane protein-glycoprotein-130 beta-subunit (gp130) and thus form IL-6 family cytokines. Proteins that may be important for cancerogenesis, CT-1, IL-11, IL-27, LIF, OSM, and CNTF, belong to the superfamily of IL-6. Cytokines such as IL-6, IL-11, and IL-27 are better investigated in comparison with other members of the same family of cytokines, eg, CT-1. Gp130 is one of the main receptors through which these cytokines exert their effects. The clinical implication of understanding the pathways of these cytokines in oncology is that targeted therapy to inhibit or potentiate cytokine activity may lead to remission in some cases.

Design, QSAR Methodology, Synthesis and Assessment of Some Structurally Different Xanthone Derivatives as Selective Cox-2 Inhibitors for their Anti-inflammatory Properties.

INTRODUCTION: Inflammation can be defined as a complex biological response that is produced by body tissues to harmful agents like pathogens, irritants, and damaged cells and thereby acts as a protective response incorporating immune cells, blood vessels, and molecular mediators. Histamine, serotonin, bradykinin, leukotrienes (LTB4), prostaglandins (PGE2), prostacyclins, reactive oxygen species, proinflammatory cytokines like IL-1, IL-11, TNF- anti-inflammatory cytokines like IL-4, IL-10, IL-11, IL-6 and IL-13, etc. all have different effects on both pro and anti-inflammatory mediators. Incorporation of combinatorial chemistry and computational studies have helped the researchers to design xanthones moieties with high selectivity that can serve as a lead compound and help develop potential compounds that can act as effective COX-2 inhibitors. The study aims to design and develop different series of substituted hydroxyxanthone derivatives with anti-inflammatory potential. METHODS: The partially purified synthetic xanthone derivatives were orally administered to the carrageenan induced paw oedemic rat models at the dose of 100 mg/kg, and their effect in controlling the degree of inflammation was measured at the time interval of 30 min, 1, 2, 3, 4 and 6 hrs. respectively. Further, these compounds were also subjected to modern analytical studies like UV, IR, NMR and mass spectrometry or their characterization. RESULTS: The results drawn out of the in silico, in vitro, in vivo and analytical studies concluded that the hydroxyxanthone derivatives can obstruct the enzyme COX-2 and produce anti-inflammatory action potentially. CONCLUSION: With the aim to evaluate the compounds for their anti-inflammatory activity, it was observed that the newly designed xanthonic compounds also possess a safe toxicity margin and hence can be utilized by the researchers to develop hybrid xanthonic moieties that can specifically target the enzyme COX-2.

Bazedoxifene Suppresses the Growth of Osteosarcoma Cells by Inhibiting IL-6 and IL-11/GP130 Signaling Pathway.

Osteosarcoma is the most common primary bone tumor. Using the multiple ligands simultaneous docking method, we found that bazedoxifene could bind to the GP130 D1 domain. We then demonstrated that bazedoxifene can decrease cell viability and cell migration of osteosarcoma cells by inhibiting interleukin 6 (IL-6) and IL-11/GP130 signaling. Consistently, treatment with IL-6 or IL-11 antibody or knockdown of GP130 by siRNA silenced the activation of STAT3, ERK, and AKT. Similarly, recombinant IL-6 and IL-11 proteins antagonized the inhibitory effect of bazedoxifene on osteosarcoma cells. Finally, the combinational treatment of temsirolimus and bazedoxifene synergistically suppressed osteosarcoma development in vitro and in vivo. Our findings suggest that bazedoxifene directly prompts the deactivation of GP130 and inhibits the osteosarcoma progression in vitro and in vivo. Therefore, bazedoxifene could be effectively applied as a therapeutic drug for human osteosarcoma in the future.