IL-1 Family Research Articles

The role of Interleukin-38 in modulating T cells in chronic Colitis: A mouse model study

BackgroundInterleukin (IL)-38 belongs to the IL-36 subfamily within the IL-1 family. Patients with inflammatory bowel diseases (IBD) exhibit higher levels of IL-38 in their intestinal tissue compared to healthy controls, suggesting that IL-38 may play a role in the pathogenesis of IBD. However, IL-38′s impact on T cell-mediated immune responses in gastrointestinal inflammation has not been investigated. Therefore, the objective of this work was to elucidate the role of IL-38 in modulating T cells in a mouse model of dextran sulfate sodium (DSS)-induced chronic colitis. MethodsRecombinant IL-38 (rIL-38) was administered intraperitoneally (i.p.) to mice with chronic colitis induced by DSS. Clinical symptoms, length of colon, and histologic alterations were assessed. Cytokine production was quantified using ELISA, and helper T (Th) cell subsets were evaluated via flow cytometry. ResultsAdministration of recombinant IL-38 (rIL-38) alleviated DSS-induced chronic colitis. In addition, animals with chronic colitis treated with rIL-38 exhibited a significant decrease in the spontaneous production of inflammatory cytokines by neutrophils in the lamina propria. Furthermore, rIL-38 treatment increased the absolute numbers and percentages of regulatory T cells (Tregs) but decreased the absolute numbers and percentages of Th1 and Th17 cells. Moreover, rIL-38 treatment also decreased IL-17A-producing γδT cells substantially. ConclusionThis study’s results show that IL-38 reduces the effects of chronic colitis caused by DSS by boosting Treg reactions and reducing Th1/Th17 reactions and IL-17A-producing γδT cells in LPL. Therefore, we propose that IL-38 has the potential to be utilized as a biological therapy agent for IBD.

Leukemia Inhibitory Factor Receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the IL-6 cytokine family, such as Interleukin-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

Host Genetic Variations and Their Implications on HBV and HCV Infection in the Iranian Population: A Comprehensive Systematic Review

Background: Background: Hepatitis virus infections are among the serious emerging health issues. They are the primary causes of cirrhosis and hepatocellular carcinoma. Growing evidence shows a link between certain genomic variations and inflammation including viral infection such as HBV and HCV. Therefore, this study aimed to comprehensively review studies that analyze the effect of host genomic variations on the risk of contracting viral hepatitis in Iranian population. Methods: The study was conducted according to the PRISMA Statement. All Persian and English case-control articles published until the beginning of June 2023 were included in the study. Two authors reviewed the articles independently. The third author reviewed the final results. Pathway analysis and protein interactions were also performed using GO and STRING databases. Results: Seventy relevant studies were retrieved. Fifty-three studies examined the association of SNPs with the risk of HBV infection. In terms of genetic variations, 25 genes and 44 SNPs were identified. Tumor necrosis factor alpha, Interleukin 28B, and Interleukin 10 were the most prevalent considered genes. The most common polymorphisms were in the interleukin family. Moreover, the top five identified molecular functions were cytokine activity, cytokine receptor binding, molecular function regulator, protein binding, and signaling receptor binding. Conclusion: The polymorphisms of genes involved in the production of immune factors, cytokines, interleukins, and their receptors are associated with the risk of HBV and HCV infections in the Iranian population. Moreover, the extracellular and intracellular signaling pathways and the regulating molecules of these processes can be considered as important factors in liability for these viral infections.

PH-Responsive Modified HAMA Microspheres Regulate the Inflammatory Microenvironment of Intervertebral Discs.

Currently, intervertebral disc (IVD) degeneration is believed to lead to local accumulation of lactic acid in the IVD, a decrease in pH, activation of the inflammatory pathway, and continued destruction of homeostasis of the IVD. To address these issues, the intelligent and accurate release of drugs is particularly important. In this study, acid-sensitive release methacrylated hyaluronic acid (HAMA) microspheres were constructed by using microfluidic technology, which can be used as a targeted drug delivery system for intervertebral disc degeneration (IVDD) through Schiff base chemical bonding on the surface of the microspheres to achieve intelligent drug release. Interleukin-1 receptor antagonist (IL-1 Ra) is a naturally occurring anti-inflammatory antagonist of the interleukin-1 family of pro-inflammatory cytokines. Despite its outstanding broad-spectrum anti-inflammatory effects, IL-1 Ra has a short biological half-life (4-6 h). The slow-release performance of IL-1 Ra can be greatly improved using bovine serum albumin nanoparticles (BNP). In addition, the modified HAMA microspheres exhibited good injectability and porosity, and efficient and uniform loading of nanoparticles was achieved via the Schiff base bond. The inflammatory microenvironment can be significantly reversed by transporting the modified HAMA microspheres-BNPs (Modified MS) to the degenerative nucleus pulposus.

IL-10 promotes Th17 cell differentiation by enhancing STAT1-dependent IL-6 production via IgE-stimulated mast cells

Mast cells (MCs) are tissue-resident cells of hematopoietic origin that play an important role in host’s defense mechanism against nematodes. However, excessive activation of these cells contributes to the development of certain allergic diseases. Immunoglobin E (IgE) is one of the well-known molecules that activate MCs. Even in the absence of specific antigens, the binding of highly cytokinergic IgE to FcεRI on MCs prolongs their survival and induces cytokine production without enhancing their degranulation. In the present study, we examined the effects of the members of the interleukin-10 (IL-10) family of cytokines on IgE-mediated MCs functions. The receptors including Il10r1, Il10r2, and Il20r2, but not Il20r1, Il22r1 or Il28r1, were constitutively expressed in mouse bone marrow cell-derived cultured MCs (BMCMCs), suggesting that IL-10 may influence MCs function. Indeed, we found that only IL-10 could influence upon BMCMCs function; IL-10 enhanced prolongation of survival, promoted IL-6 and/or IL-13 production dependently of STAT1 and STAT3, and suppressed tumor necrosis factor production independently of STAT1 and STAT3 on IgE-stimulated BMCMCs. Moreover, the IL-10-mediated enhancement of IL-6 production by IgE-stimulated BMCMCs promotes Th17 cell expansion. These results suggest that IL-10 has a dual role as an anti-inflammatory and pro-inflammatory cytokine in MCs functions.

Interleukin-11 signaling plays limited roles for liver fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis

Liver fibrosis, an abnormal accumulation of collagen fibers in the liver, is caused due to several chronic liver diseases including viral hepatitis, alcoholic steatohepatitis, and metabolic dysfunction-associated steatohepatitis. Among the various symptoms of chronic hepatitis, liver fibrosis is the most crucial factor in determining patient prognosis. Extensive liver fibrosis leads to cirrhosis and liver cancer and shortens the lifespans of patients. However, no drug is currently approved for the treatment of liver fibrosis. Therefore, the identification of molecular mechanisms and druggable targets of liver fibrosis is urgently needed. Interleukin-11 is a member of the interleukin-6 family of inflammatory cytokines that is involved in multiple processes of inflammation and tissue repair. Recent reports also suggest the pro-fibrogenic function of interleukin-11 in various organs. In this study, we examined the fibrogenic potential of interleukin-11 in the liver using a choline-deficient, amino acid-defined high-fat diet, a mouse model of metabolic dysfunction-associated steatohepatitis that rapidly develops liver fibrosis. Although interleukin-11 was specifically upregulated in the liver in this pathological model, the loss of interleukin-11 signaling played minor roles in liver injury, inflammation, fibrosis, and signal transduction pathways. Our results indicate that the pro-fibrogenic function of interleukin-11 may vary among organs and disease etiologies.

Transpulmonary proteome gradients identify inflammatory pathways involved in the development of pulmonary vasculopathy in heart failure

Abstract Background Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify not only markers but also mediators of PVD by identifying proteins that may be consumed or elaborated across the lungs. Purpose Examine hemodynamics and transpulmonary proteome gradients in HFrEF and controls. Methods 21 non-HF controls and 160 patients with advanced HFrEF underwent pulmonary artery (PA) catheterization with blood sampling from the PA catheter in the wedged position (02sat > 90%, indicating pulmonary venous blood) and the un-wedged position to obtain transpulmonary proteome gradients. Samples from controls and HF from the highest quartile (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic PEA assay of 275 proteins (Olink Target 96, panels CVII, CVIII, Inflammation). Pulmonary artery concentrations ("markers") or transpulmonary fold-change gradients (i.e. putative "mediators") of normalized protein expression (NPX) were plotted against significance; Benjamini–Hochberg FDR<0.05 considered as significant. Results Patients displayed typical characteristics of HFrEF (age 56±8y, NYHA 3.0 ±0.6, 87% males, LVEF 24±9.6%), Controls had similar anthropometrics, gender and age. Comparing all HF to Con, 38 markers of HF were identified (NPX fold-change>2), including 33 up (top 5: NTproBNP, BNP, GDF15, FGF23, IL8) and 5 down. HF patients in Q1 had median PVR 1.5 (IQR: 0.3-1.7) WU and those in Q4 had PVR 5.4 (4.3-6.6) WU. Comparison of Q1 and Q4 identified 3 protein markers of high PVR in PA blood from HF: chemokine CCL3, TNFRSF13B and surfactant protein-D (PSP-D). Examination of protein gradients from HF lungs (Figure) showed significant uptake of 14 protein mediators, most of which were associated with inflammatory responses (top 5: OSM, MMP9, CCL19, BNP, TR), and release of 8 mediators (top 4: IL-6, IL33, CCL4, CXCL10). In contrast, protein gradients were negligible in controls. Patients in Q4 PVR group were characterized by the highest pulmonary uptake of OSM (Oncostatin-M), lymphatic chemokine CCL19, BNP, MMP9, and had more significant transpulmonary release of IL6 and IL33. Across all patients, OSM lung uptake was the strongest correlate of transpulmonary pressure gradient (r=-0.3, p<0.001). Conclusions Lungs of patients with HF, and particularly those with high PVR, display abnormal uptake and release of proinflammatory CC and CXC chemokines and cytokines from IL1 and IL6 family, along with increased pulmonary uptake of IL6-type cytokine Oncostatin-M, a known mediator of lung inflammation and fibrosis, that acts via gp130/JAK/STAT, suggesting a novel role in PVD due to HF.Transpulmonary proteome in HF patients

The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis.

Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor α subunit (IL-11Rα) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11Rα are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.

Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages.

Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular Salmonella replication within human macrophages.

The role of IL-17 family cytokines in cardiac fibrosis.

Myocardial fibrosis is a common pathological feature in various cardiovascular diseases including myocardial infarction, heart failure, and myocarditis. Generally, persistent myocardial fibrosis correlates with poor prognosis and ranks among the leading causes of death globally. Currently, there is no effective treatment for myocardial fibrosis, partly due to its unclear pathogenic mechanism. Increasing studies have shown IL-17 family cytokines are strongly associated with the initiation and propagation of myocardial fibrosis. This review summarizes the expression, action, and signal transduction mechanisms of IL-17, focusing on its role in fibrosis associated with cardiovascular diseases such as myocardial infarction, heart failure, hypertension, diabetes, and myocarditis. It also discusses its potential as a therapeutic target, offering new insights for the clinical treatment of myocardial fibrosis.

The role of selected cytokines from the interleukin-1 family in the peritoneal fluid of women with endometriosis.

Endometriosis is a complex, chronic inflammatory disease in which immune system disorders play an important role. Soluble mediators of the immune and inflammatory response, including cytokines, are involved in these processes. Therefore, the aim of the conducted research was to understand the role of selected cytokines belonging to the Interleukin-1(IL-1) family, including IL-36α, IL-36β, IL-36γ, IL-36R, IL-37 and IL-38, in the onset and development of endometriosis by analysing the concentration of the tested molecules and to determine whether their concentration depends on the stage of the disease. The study group included 60 women who had pelvic endometriosis diagnosed during laparoscopy and subsequently confirmed by histopathology. The reference group consisted of 20 women who had no endometriosis or other pelvic lesions during laparoscopy. Immunoenzymatic assays were used to determine the concentration of the cytokines studied. In the peritoneal fluid of women with endometriosis, a statistically significant increase in the concentrations of all parameters tested was observed: IL-36α, IL-36β, IL-36γ, IL-36R, IL-37 and IL-38. The concentration of these cytokines depended on the severity of the disease. Disturbances of the immune system involving the network of cytokines belonging to the IL-1 family occurring in the peritoneal fluid environment testify to the involvement of these molecules in the development of the disease and are one of many factors involved in the pathogenesis of endometriosis. The use of some of them in the treatment of endometriosis may be a hope for effective causal treatment of this disease, but this requires further, more advanced research.

Vaccinia virus F1Lblocks the ribotoxic stress response to subvert ZAKα-dependent NLRP1 inflammasome activation.

Inflammasomes are essential for host defense, recognizing foreign or stress signals to trigger immune responses, including maturation of IL-1 family cytokines and pyroptosis. Here, NLRP1 is emerging as an important sensor of viral infection in barrier tissues. NLRP1 is activated by various stimuli, including viral double-stranded (ds) RNA, ribotoxic stress, and inhibition of dipeptidyl peptidases 8 and 9 (DPP8/9). However, certain viruses, most notably the vaccinia virus, have evolved strategies to subvert inflammasome activation or effector functions. Using the modified vaccinia virus Ankara (MVA) as a model, we investigated how the vaccinia virus inhibits inflammasome activation. We confirmed that the early gene F1L plays a critical role in inhibiting NLRP1 inflammasome activation. Interestingly, it blocks dsRNA and ribotoxic stress-dependent NLRP1 activation without affecting its DPP9-inhibition-mediated activation. Complementation and loss-of-function experiments demonstrated the sufficiency and necessity of F1L in blocking NLRP1 activation. Furthermore, we found that F1L-deficient, but not wild-type MVA, induced ZAKα activation. Indeed, an F1L-deficient virus was found to disrupt protein translation more prominently than an unmodified virus, suggesting that F1L acts in part upstream of ZAKα. These findings underscore the inhibitory role of F1L on NLRP1 inflammasome activation and provide insight into viral evasion of host defenses and the intricate mechanisms of inflammasome activation.

Interleukin 38 reduces antigen-presentation capacity and antibody production after vaccination

The mechanisms that underpin low vaccine responses, which can lead to inadequate protection against infection, are still partially unclear. Interleukin (IL)-38 is a member of the IL-1 family, expressed by B cells among others, that regulates inflammatory responses. A recent study shows that IL-38 suppresses plasma cell generation and antibody production upon immune activation.We hypothesis that IL-38 affects antigen-presentation capacity of innate immune cells, effecting antibody production. Here, we investigated the effect of recombinant human IL-38 on human peripheral blood mononuclear cells and myeloid-derived DCs regarding cytokine production, phagocytosis, and expression of MCH II and co-stimulatory proteins in vitro, and further relate circulating plasma IL-38 concentrations to antibody responses in a cohort of 75 females aged 18–48 vaccinated with BCG and Tdap-IPV.To this end, we found that IL-38 decreased the expression of HLA-DR, HLA-DM, and CD83 on PBMCs, and CD40 and CD86 on MDDCs. IL-38 further impaired phagocytosis capacity of monocytes. Lastly, antibody production against diphtheria toxoids up to eight months post-vaccination was negatively associated with IL-38 plasma concentrations.These data suggest that IL-38 could dampen the effectiveness of antigen-presentation and phagocytosis, and could therefore modulate the immunogenicity of some vaccine types.

Expanding Role of Interleukin-1 Family Cytokines in Acute Ischemic Stroke.

Ischemic stroke (IS) is a critical medical condition that results in significant neurological deficits and tissue damage, affecting millions worldwide. Currently, there is a significant lack of reliable tools for assessing and predicting IS outcomes. The inflammatory response following IS may exacerbate tissue injury or provide neuroprotection. This review sought to summarize current knowledge on the IL-1 family's involvement in IS, which includes pro-inflammatory molecules, such as IL-1α, IL-1β, IL-18, and IL-36, as well as anti-inflammatory molecules, like IL-1Ra, IL-33, IL-36A, IL-37, and IL-38. The balance between these opposing inflammatory processes may serve as a biomarker for determining patient outcomes and recovery paths. Treatments targeting these cytokines or their receptors show promise, but more comprehensive research is essential to clarify their precise roles in IS development and progression.

Nasal microbionts differentially colonize and elicit cytokines in human nasal epithelial organoids.

Nasal colonization by Staphylococcus aureus or Streptococcus pneumoniae is associated with an increased risk of infection by these pathobionts, whereas nasal colonization by Dolosigranulum species is associated with health. Human nasal epithelial organoids (HNOs) physiologically recapitulate human nasal respiratory epithelium with a robust mucociliary blanket. We reproducibly monocolonized HNOs with these three bacteria for up to 48 hours with varying kinetics across species. HNOs tolerated bacterial monocolonization with localization of bacteria to the mucus layer and minimal cytotoxicity compared to uncolonized HNOs. Human nasal epithelium exhibited both species-specific and general cytokine responses, without induction of type I interferons, consistent with colonization rather than infection. Only live S. aureus colonization induced IL-1 family cytokines, suggestive of inflammasome signaling. D. pigrum and live S. aureus decreased CXCL10, whereas S. pneumoniae increased CXCL11, chemokines involved in antimicrobial responses. HNOs are a compelling model system to reveal host-microbe dynamics at the human nasal mucosa.

Interleukin signaling in the regulation of natural killer cells biology in breast cancer.

In the field of breast cancer treatment, the immunotherapy involving natural killer (NK) cells is increasingly highlighting its distinct potential and significance. Members of the interleukin (IL) family play pivotal regulatory roles in the growth, differentiation, survival, and apoptosis of NK cells, and are central to their anti-tumor activity. These cytokines enhance the ability of NK cells to recognize and eliminate tumor cells by binding to specific receptors and activating downstream signaling pathways. Furthermore, interleukins do not function in isolation; the synergistic or antagonistic interactions between different interleukins can drive NK cells toward various functional pathways, ultimately leading to diverse outcomes for breast cancer patients. This paper reviews the intricate relationship between NK cells and interleukins, particularly within the breast cancer tumor microenvironment. Additionally, we summarize the latest clinical studies and advancements in NK cell therapy for breast cancer, along with the potential applications of interleukin signaling in these therapies. In conclusion, this article underscores the critical role of NK cells and interleukin signaling in breast cancer treatment, providing valuable insights and a significant reference for future research and clinical practice.

IL-33 in Ischemic Stroke: Brainvs.Periphery.

Cerebrovascular disease is the second-leading cause of death and disability worldwide, with stroke being the most common cause. In ischemic stroke, several processes combine to produce immunosuppression, leaving the post-stroke body susceptible to infection, which in turn affects neuroinflammation. Interleukin-33 (IL-33), a member of the interleukin-1 family (IL-1), functions as a modulator of immune responses and inflammation, playing a crucial role in the establishment of immunologic responses. IL-33 has been shown to have a protective effect on brain injury and represents a potential target by modulating inflammatory cytokines and stimulating immune regulatory cells. With an emphasis on preclinical and clinical studies, this review covers the impact of IL-33 on immune system mechanisms following ischemic stroke.

Characterization of the angiomodulatory effects of Interleukin 11 cis- and trans-signaling in the retina

BackgroundThe IL-6 cytokine family, with its crucial and pleiotropic intracellular signaling pathway STAT3, is a promising target for treating vasoproliferative retinal diseases. Previous research has shown that IL-6 cis-signaling (via membrane-bound receptors) and trans-signaling (via soluble receptors) can have distinct effects on target cells, leading to their application in various disease treatments. While IL-6 has been extensively studied, less is known about the angiogenic effects of IL-11, another member of the IL-6 family, in the retina. Therefore, the aim of this study was to characterize the effects of IL-11 on retinal angiogenesis.Main textIn vitreous samples from proliferative diabetic retinopathy (PDR) patients, elevated levels of IL-11Rα, but not IL-11, were detected. In vitro studies using vascular endothelial cells revealed distinct effects of cis- and trans-signaling: cis-signaling (IL-11 alone) had antiangiogenic effects, while trans-signaling (IL-11 + sIL-11Rα) had proangiogenic and pro-migratory effects. These differences can be attributed to their individual signaling responses and associated transcriptomic changes. Notably, no differences in cis- and trans-signaling were detected in primary mouse Müller cell cultures. STAT3 and STAT1 siRNA knockdown experiments revealed opposing effects on IL-11 signaling, with STAT3 functioning as an antiproliferative and proapoptotic player while STAT1 acts in opposition to STAT3. In vivo, both IL-11 and IL-11 + sIL-11Rα led to a reduction in retinal neovascularization. Immunohistochemical staining revealed Müller cell activation in response to treatment, suggesting that IL-11 affects multiple retinal cell types in vivo beyond vascular endothelial cells.ConclusionsCis- and trans-signaling by IL-11 have contrasting angiomodulatory effects on endothelial cells in vitro. In vivo, cis- and trans-signaling also influence Müller cells, ultimately determining the overall angiomodulatory impact on the retina, highlighting the intricate interplay between vascular and glial cells in the retina.

Evaluation of Interleukin-6 Levels in Patients with Type 2 Diabetes Mellitus

Background: It has been suggested that inflammatory processes play an important role in the pathogenesis of type 2 diabetes. Individuals who develop type 2 diabetes show signs of low-grade inflammation years before disease onset. This low-grade inflammation has been assumed to be implicated in the pathogenetic mechanisms that cause type 2 Diabetes Mellitus. Inflammatory mediators such as the IL-6 family of cytokines have been proposed to be involved in the events that lead to type 2 diabetes. IL-6 has immunoregulatory actions been proposed to affect glucose homeostasis and metabolism directly and indirectly by action on skeletal muscle cells, adipocytes, hepatocytes, pancreatic b-cells and neuroendocrine cells. Many studies have suggested the role of IL-6 in the pathogenesis of type 2 diabetes mellitus. However, no references have been observed in Bangladesh regarding IL-6 and its association with type 2 diabetes mellitus. It thus may highlight the importance of low-grade inflammation in the pathophysiology of type 2 diabetes mellitus. The purpose of this study was to evaluate type 2 diabetes patients' levels of interleukin-6. Materials and methods: A hospital-based cross-sectional observational study was carried out in the Department of Biochemistry Chittagong Medical College, Department of Endocrinology of Chittagong Medical College Hospital and Chattogram Diabetic Hospital. One hundred (100) type 2 diabetes mellitus patient was included in the study by nonprobability consecutive sampling. Important variables in this study were serum IL-6, BMI, waist circumference and duration of Diabetes Mellitus. Results: The mean serum IL-6 level was 10.08±0.39 pg/ml in patients with type 2 Diabetes Mellitus. Serum IL-6 was positively correlated (r 0.33, p <0.01) with waist circumference and duration of diabetes mellitus (r 0.26, p <0.05). The mean IL-6 was significantly different between BMI groups (F (2,97) =5.39, p=0.006) and was higher in the obese group (10.52±4.00) compared to the overweight and normal BMI (6.78±1.95) and overweight (8.08±3.15) group. Conclusion: It can be concluded that type 2 diabetes mellitus patients had increased serum levels of IL-6. It can give an insight into the possible role of sub clinical inflammation among patients with type 2 Diabetes Mellitus. IAHS Medical Journal Volume 6(2) December 2023; 53-57

Abstract A060: Dysregulation of PTEN expression in a subset of Cancer Associated Fibroblasts by Tumor Secreted Factors in PDAC

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy. Cancer associated fibroblasts (CAFs) play a complex role in the PDAC tumor microenvironment (TME), with a subset contributing significantly to tumor progression. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss is associated with increased tumor aggressiveness. Our group previously demonstrated PTEN loss in SMA+ positive CAFS correlated with worsened outcomes in patients and in mouse PDAC models. Our group previously demonstrated the loss of PTEN in CAFS led to activation of Stat3, resulting in an immunosuppressive microenvironment (Lefler et al, 2022 PMID: 35803738). However, little is known of the signals produced by tumor cells or other cell types in the TME that trigger loss of PTEN in CAFs. This study aims to to elucidate the molecular mechanisms underlying PTEN loss in CAFs in PDAC. To address this gap, we employed single cell RNA sequencing of tumors from a mouse PDAC model and identified a (PDRGFRa+Lys6+Stat3+Pten-low) CAF subpopulation. Comparing normal pancreas epithelial cells to tumor cells in this data set, we identified the IL6 family of cytokines, (IL6; Oncostatin-M, OSM; and Leukemia Inhibitory Factor, LIF) and Transforming Growth Factor beta 1 (TGFb1) as potential ligands that regulated PTEN, while myeloid cells were a source of the IL6 family member Oncostatin M (OSM). Treatment of isolated CAFs with these factors revealed no significant difference in PTEN mRNA expression. Thus, we developed an in vitro reporter system in which a PTEN-GFP fusion protein is expressed in CAFs. Treating these CAFs with IL6, OSM and TGFb1 (but not LIF) led to a significant decrease in GFP fluorescence. Analysis of endogenous PTEN by western blot confirmed these results. We posited that expression of PTEN E3 ligases might be increased by treatment with these factors, leading to destruction of PTEN. In support of this hypothesis, the expression of E3 ligases WWP1 and WWP2 was increased by treatment with IL6 and OSM. Additionally, preliminary data has revealed that PTEN is oxidized in isolated CAFs, which causes loss of PTEN activity and potentially increased protein turnover. Current experiments are aimed at testing these potential mechanisms. To conclude, PTEN is dysregulated post-transcriptionally in CAFs. The mechanism of PTEN dysregulation could be via increased expression of E3 ligases that target PTEN and/or PTEN oxidation. Future efforts will be aimed at testing whether inhibition of these pathways can restore PTEN expression in mouse PDAC models. These pathways and interactions could be further exploited for therapeutic benefit in curbing PDAC progression. Citation Format: Ivo N. Woogeng, Lu Han, Samaneh Saberi, Cameron Bumbleburg, Joseph Beaudet, Sudarshana Sharma, Michael Ostrowski. Dysregulation of PTEN expression in a subset of Cancer Associated Fibroblasts by Tumor Secreted Factors in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A060.