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Copyright of Kufa Medical Journal is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims: This study aimed to investigate the effect of interleukin-35 (IL-35) on inflamed lung tissue in a murine model of asthma. IL-35 was examined for its potential to induce regulatory lymphocytes during ovalbumin (OVA)-induced acute lung injury. Methods: Female BALB/c mice sensitized with OVA and were treated with recombinant IL-35 (rIL-35) via intranasal or intraperitoneal routes and were administered 4 h before OVA challenge. The effects of rIL-35 treatment on the lung and blood levels of regulatory B cells (Bregs) and regulatory T cells (Tregs), as well as their production of immunosuppressive cytokines, were determined using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. Results: Treatment of OVA-sensitized asthmatic mice with rIL-35, whether administered intranasally or intraperitoneally, resulted in reduced lung inflammation and injury. This reduction was accompanied by an increase in the frequency of IL-35 producing Bregs, IL-35 and IL-10 producing Bregs, and conventional LAG3+ Tregs in the lung tissues and blood. This increase was more pronounced with intranasal rIL-35. Furthermore, there was a positive correlation between the levels of these regulatory cells and lung gene expression of IL-35 and IL-10, and an inverse correlation with both lung gene expression and plasma level of IL-17. Conclusions: The results of this study suggest that IL-35, through its ability to increase Bregs and Tregs, is effective in reversing lung inflammation in the context of asthma. Since the increase was more pronounced with intranasal administration, this highlights the therapeutic potential of its local intrapulmonary application in managing asthma-related inflammation. [ABSTRACT FROM AUTHOR]

The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1). Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35+ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches. FA mice had a lower frequency of IL-35+ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA. The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1. • The frequency of Breg cells was lower in FA mice. • The quantity of IL-35 was lower in intestinal Breg cells from FA mice. • Inhibition of DNMT1 attenuated experimental FA. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA), is a disease that happened because autoimmune and inflammatory effects, it is mean that the human immune system offence healthy cells in the body mistakenly, resulting in inflammation (swelling) in the impacted portions of the body. Osteoarthritis (OA) is treated as the most famous form of joint arthritis. Objective: It is a slowly developed, disabling joint problem that decrease quality of life (QOL) and affects 14% of adults ages 25 and older and nearly 34% of those ages 65 and older. Interleukin elevation levels have been linked to autoimmune and degenerative diseases, thus in the current study. Methods: We tried to evaluate the level of interleukins (IL-35 and IL-38) in the two diseases and found the relationship between immune system response and disease severity. Three groups (RA, OA and control) have been used in the study. Results: The comparison between the three groups has been done and the results show a high significant increase in the level of IL-35 and IL-38 in both patients groups (RA and OA) as compared with control (p<0.001). Furthermore, a highly significant (p<0.001) elevated Na level with a significant (p<0.001) decrease in K and Ca levels was found in the RA and OA patients compared with the control. Conclusions: The study shows that the rise in the levels of IL-35 and IL-38 declares the instinctive role of interleukins and the immune system in the regulation and severity of RA and OA diseases, the role of this parameter may be clear in the controlling and monitoring the progression of diseases. [ABSTRACT FROM AUTHOR]

Gut microbiota/metabolites not only participate in the food and energy metabolism but also contribute to the host immune response and homeostasis. The alternation of gut microbiota/metabolites has been widely related to intestinal and extra-intestinal disorders such as intestinal bowel diseases (IBDs). Bactericidal substances from gut epithelial cells can regulate the composition of gut microbiota. However, the effects of regenerating protein 4 (REG4) (human)/(Reg4) (mice), a potentially bactericidal substance from gut epithelial cells, on the gut immune homeostasis maintain elusive. Here, we found that REG4/Reg4 is essential in maintaining gut immune homeostasis through REG4/Reg4 associated gut microbiota. Reg4 knockout (KO) mice were highly sensitive to DSS-mediated colitis, whereas human REG4 intestine epithelial cell transgenic (huREG4IECtg) mice exhibited more resistance to DSS-mediated colitis. Mechanistically, sequencing of gut microbiota and liquid chromatography-mass spectrometry showed that REG4/Reg4 could affect the composition of gut microbiota. REG4/Reg4 associated gut microbiota such as Lactobacillus could metabolize linoleic acid (LA) into conjugated linoleic acid (CLA). Immunoprecipitation and immunoblot showed that CLA could effectively promote the expression of IL-35 in macrophages through Gαq/11 mediated activation STAT1/4. Thus, our results demonstrate that REG4/Reg4 plays a critical role in maintaining gut immune homeostasis through CLA-mediated IL-35+ macrophages.

Background: Rheumatoid arthritis (RA), is a disease that happened because autoimmune and inflammatory effects, it is mean that the human immune system offence healthy cells in the body mistakenly, resulting in inflammation (swelling) in the impacted portions of the body. Osteoarthritis (OA) is treated as the most famous form of joint arthritis. Objective: It is a slowly developed, disabling joint problem that decrease quality of life (QOL) and affects 14% of adults ages 25 and older and nearly 34% of those ages 65 and older. Interleukin elevation levels have been linked to autoimmune and degenerative diseases, thus in the current study. Methods: We tried to evaluate the level of interleukins (IL-35 and IL-38) in the two diseases and found the relationship between immune system response and disease severity. Three groups (RA, OA and control) have been used in the study. Results: The comparison between the three groups has been done and the results show a high significant increase in the level of IL-35 and IL-38 in both patients groups (RA and OA) as compared with control (p

Background: Thyroid‐associated ophthalmopathy (TAO) is the most common orbital disease in adults, potentially leading to disfigurement and visual impairment. However, the causes of TAO are not fully understood. IL‐35+B cells are a newly identified regulatory B cells (Bregs) in maintaining immune balance in various autoimmune diseases. Yet, the influence of IL‐35+Bregs in TAO remains unexplored. Methods: This study enrolled 36 healthy individuals and 14 TAO patients. We isolated peripheral blood mononuclear cells and stimulated them with IL‐35 and CpG for 48 h. Flow cytometry was used to measure the percentages of IL‐35+Bregs. Results: The percentage of circulating IL‐35+Bregs was higher in TAO patients, and this increase correlated positively with disease activity. IL‐35 significantly increased the generation of IL‐35+Bregs in healthy individuals. However, B cells from TAO patients exhibited potential impairment in transitioning into IL‐35+Breg phenotype under IL‐35 stimulation. Conclusions: Our results suggest a potential role of IL‐35+Bregs in the development of TAO, opening new avenues for understanding disease mechanisms and developing therapeutic approaches. [ABSTRACT FROM AUTHOR]

Inflammatory cytokines have crucial roles in the pathogenesis of tuberculosis (TB), and interleukin (IL)-27 and IL-35 have a pro-inflammatory and antiinflammatory effect on many diseases, including infectious diseases. Therefore, we evaluated the relationship between IL-27 and IL-35 gene polymorphism, expression levels, and pulmonary TB (PTB) susceptibility. Nine single-nucleotide polymorphisms (SNPs) in the IL-27 gene (rs181206, rs153109, and rs17855750) and the IL-35 gene (rs4740, rs428253, rs9807813, rs2243123, rs2243135, and rs568408) were genotyped by the SNPscan technique in 497 patients with PTB and 501 controls. There was no significant difference regarding the genotype and allele frequencies of the above SNPs in the IL-27 and IL-35 genes between patients with PTB and controls. Haplotype analysis showed that the frequency of the GAC haplotype in the IL-35 gene was significantly decreased in patients with PTB when compared to controls (p=0.036). Stratified analysis suggested that the frequency of the IL-27 rs17855750 GG genotype was significantly increased in patients with PTB with fever. Moreover, the lower frequency of the IL-35 rs568408 GA genotype was associated with drug-induced liver injury in patients with PTB. The IL-35 rs428253 GC genotype, as well as the rs4740 AA genotype and A allele, showed significant relationships with hypoproteinemia in patients with PTB. When compared with controls, the IL-27 level was significantly increased in patients with PTB. Taken together, IL-35 gene variation might contribute to a protective role on the susceptibility to PTB, and IL-27 and IL-35 gene polymorphisms were associated with several clinical manifestations of patients with PTB. [ABSTRACT FROM AUTHOR]

Recent findings have shown that the level of interleukin‐35 (IL‐35) is abnormal in several autoimmune diseases. Nonetheless, whether IL‐35 participates in the pathogenesis of immune thrombocytopenia (ITP) remains unclear. The current study investigates whether IL‐35 modulates megakaryopoiesis. The results show that IL‐35 receptors are progressively expressed on bone marrow megakaryocytes during the in vitro differentiation of CD34+ progenitors. IL‐35 increases the number of megakaryocyte colony‐forming units through the Akt pathway. The level of bone marrow IL‐35 is reduced in ITP patients, and the decreased level of IL‐35 may inhibit megakaryopoiesis. Then, the potential causes of decreased IL‐35 in ITP patients are explored. The primary type of cell that secretes IL‐35, known as IL‐35‐producing regulatory T cells (iTr35), is reduced in ITP patients. Bone marrow mesenchymal stem cells (MSCs) from ITP patients exhibit an impaired capability of inducing iTr35 due to enhanced apoptosis, which may contribute to the reduced level of bone marrow IL‐35 in ITP patients. Iguratimod promotes megakaryocyte development and differentiation by elevating the expression of IL‐35 receptors on megakaryocytes. Iguratimod improves response rates and reduces bleeding symptoms in corticosteroid‐resistant ITP patients. [ABSTRACT FROM AUTHOR]

Introduction: Severe asthma has a poor response to hormone therapy and a poor level of control, so the discovery of new pathogenetic mechanisms is important for diagnosing and treating severe asthma. IL-35 may play a protective role in autoimmune diseases by directly or indirectly inhibiting the secretion of IL-17, which is an important proinflammatory factor involved in the occurrence and development of autoimmune diseases. The autologous serum skin test (ASST) is a good sensitivity and specificity screening test for autoimmune functional autoantibodies. We compared the levels of IL-35 and IL-17 in serum samples, the positive rate of ASST, the level of exhaled nitric oxide (FeNO), and the atopic constitution in patients with severe asthma to those with mild-to-moderate asthma so as to explore the possible autoimmune pathogenesis of severe asthma. Methods: Patients with mild-to-moderate and severe asthma were enrolled. Their age, gender, smoking history, family history of asthma, history of allergic rhinitis, positive allergen results, serum total IgE (TlgE), allergen-specific IgE (slgE), routine blood, ASST results, and FeNO test results were compared and analyzed. The IL-35 and IL-17 levels in serum samples from both groups were measured by enzyme-linked immunosorbent assay for comparison and analysis. The SPSS 22.0 software package was used for statistical analysis. Results: A total of 50 patients with mild-to-moderate asthma and 31 patients with severe asthma were included in this study. The proportion of patients with a history of smoking and a family history of asthma was significantly higher in the severe asthma group compared to the mild-to-moderate asthma group (all p < 0.05); the number of positive allergen tests was significantly lower in patients with severe asthma compared to those with mild-to-moderate asthma (p < 0.001). The rate of positive ASST was significantly higher in patients with severe asthma than in patients with mild-to-moderate asthma (p < 0.05). Serum IL-17 levels were significantly higher in patients with severe asthma than in patients with mild-to-moderate asthma (p < 0.05), but serum IL-35 level between the two group was not significantly different (p = 0.113). ASST-positive patients had a statistically significant increase in the risk of developing severe asthma, while patients with allergen positive were less likely to develop severe asthma (positive ASST: OR = 5.277, p = 0.024; allergen positivity: OR = 0.123, p = 0.001). Conclusions: IL-35 has a weaker inhibitory effect on high IL-17 expression in patients with severe asthma, and the rate of positive ASST was significantly higher in patients with severe asthma, which all suggested the possibility of autoimmune pathogenesis in patients with severe asthma. [ABSTRACT FROM AUTHOR]

The aim was to investigate the therapeutic effect of bone marrow mesenchymal stem cells (BM-MSC) on dextran sulfate sodium (DSS) induced colitis in rats and its effect on regulatory T cells (Treg). A model of DSS-induced colitis was established. BM-MSC was isolated and cultured to observe the efficacy of BM-MSC on colitis, including general vital signs, weight changes, colonic length changes, colonic histopathological changes, and colonic tissue MPO activity. The expression of inflammatory factors (IFN-γ, IL-4, IL-17, TGF-β) in colonic tissues was measured by real-time PCR. The amount of CD4 + CD25 + Treg was detected by flow cytometry. Real-time PCR was used to detect Foxp3+mRNA in CD4 + CD25 + Treg, western to detect Foxp3+protein expression in CD4 + CD25 + Treg, and ELISA was used to detect IL-35 and IL-10 cytokines in CD4 + CD25 + Treg culture supernatant. Results show that intravenous injection of BM-MSC significantly improved the clinical manifestations and histopathological changes in rats with experimental DSS colitis; significantly down-regulated the expression of inflammatory factors IFN-γ, IL-4, and IL-17 and up-regulated the expression of TGF-β in colon tissues; BM-MSC also increased the number of CD4+CD25+Foxp3+Treg and enhanced the function of CD4+CD25+Foxp3+Treg in colon tissues, and up-regulated the expression of IL-35. In conclusion, BM-MSC has a certain therapeutic effect on DSS-induced colitis. It can improve the general signs of colitis rats and reduce intestinal injury and inflammatory response. The immunoregulatory effect of BM-MSC is achieved by enhancing the function of CD4+CD25+Foxp3+Treg and up-regulating the secretion of immunosuppressive inflammatory factors. Bone marrow mesenchymal stem cells has a certain therapeutic effect on dextran sulfate sodium-induced colitis. It can improve the general signs of colitis in rats and reduce intestinal injury and inflammatory response. The immunoregulatory effect of bone marrow mesenchymal stem cells is achieved by enhancing the function of CD4+CD25+Foxp3+Treg and up-regulating the secretion of immunosuppressive inflammatory factors. Graphical Abstract [ABSTRACT FROM AUTHOR]

The study examines the impact of TNF-α and IL35 levels in saliva on rheumatoid arthritis. It compares responder and non-responder patients, including 30 who responded to treatment and 30 who did not. The study found that rheumatoid arthritis incidence is three times higher in females than males. The age difference between RA patients and healthy controls was significant. TNF-α and IL35 levels were found to be highly significant in two patient groups compared to the control group. The study suggests that salivary TNF-α and IL35 levels can be used to study methotrexate effectiveness and disease activity. [ABSTRACT FROM AUTHOR]

Background: Knowing which patients would be more likely to die is crucial for making better use of the little resources available. To do this, the ability of several inflammatory indicators to identify mortality outcomes has been detected. Materials and methods: A total of 125 severe/critical COVID-19 patients were involved in this work divided into two groups based on survival, dead group (62 patients) and live group (63 patients). Between March 2022 and July 2022, these patients were admitted to Marjan medical city and Al-Sadeq hospital. Patients were determined as severe cases according to the guidelines released by National Health World. The inflammatory cytokine (IL-35) was detected by the ELISA technique.Results: IL-35 showed no statistical differences between lived 6.85 (5.44- 8.72) ng/ml and dead 6.53 (5.82- 7.89) ng/ml patients (p= 0.79). D dimer, and ferritin increased significantly in dead patients 2467.5 (1368. 7- 3697) ng/ml and 1621.5 (792.3- 2359) ng/ml respectively compared to live patients 557 (430- 689) ng/ml and 268 (186- 449) ng/ml respectively (P < 0.0001). The ROC or area under the curve (AUC) for D-dimer was 0.89 with high sensitivity (95%) and specificity (77%). Ferritin also showed a large AUC that was 0.90 with high sensitivity and specificity (95%) and (81%) respectively. The cut off point for both D- dimer and ferritin was 693.67 ng/ml and 475 ng/ml respectively. Conclusions: IL-35 revealed no significant differences between dead and lived patients with COVID-19 (p = 79). Positive strong correlation observed between ferritin and D-dimer (r= 0.85, p< 0.0001). No correlation was found between IL-35 and both ferritin and D-dimer (p > 0.05).

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.

The aim of this study was to analyze the relationship between immunological markers and the dysfunction of cutaneous microcirculation in young patients with type 1 diabetes. The study group consisted of 46 young patients with type 1 diabetes and no associated complications. Microvascular function was assessed with the use of nail fold capillaroscopy before and after implementing post-occlusive reactive hyperemia. This evaluation was then repeated after 12 months. Patients were divided into two subgroups according to their baseline median coverage (defined as the ratio of capillary surface area to surface area of the image area), which was established during the initial exam (coverageBASE). Additionally, the levels of several serum biomarkers, including VEGF, TNF-a and IL-35, were assessed at the time of the initial examination. HbA1c levels obtained at baseline and after a 12-month interval were also obtained. Mean HbA1c levels obtained during the first two years of the course of the disease were also analyzed. Patients with coverageBASE below 16.85% were found to have higher levels of VEGF and TNF-α, as well as higher levels of HbA1c during the first two years following diabetes diagnosis. Our results support the hypothesis that the development of diabetic complications is strongly influenced by metabolic memory and an imbalance of pro- and anti-inflammatory cytokines, regardless of achieving adequate glycemic control. [ABSTRACT FROM AUTHOR]

Endometrial Cancer (EC) is one of the most common malignancy of the female reproductive system. With an increasing incidence, it is important to improve the new prognosis ways for its pre-diagnosis that must be early, accurate and effective. This study aimed to search for biological (like some new interleukins) which could help in early diagnosis of EC before the hysterectomy. Currently not enough research is being done exploiting linking between the interleukins submitted in this study and EC. Epically IL-36 and IL-38, which have been recently described and are still under study in the world. This study is the first of its kind in Iraq. Fifty-five patients with EC (mainly in their first or second stage, due to early diagnosis and who newly have the symptoms and pain as a result of cancer) and 57 healthy controls (with ages up to 45) were involved in this study. To measure the concentration of the following interleukins: IL-27, 31, 33, 35, 36 and 38 by ELISA, blood samples were collected from women via vein puncture. The results of this study showed a highly significant (P≤0.01) increase in Interleukin 27 (IL-27), Interleukin 31 (IL-31) and Interleukin 33 (IL-33) among all studied interleukins levels in EC patient as compared with healthy controls. Interleukin 35 (IL-35), Interleukin 36 (IL-36) and Interleukin 38 (IL-38) also showed highly significant (P≤0.01) increase in EC patients as compared with healthy women. The significant increase (P≤0.01) of these interleukins can be used to help in the early diagnosis and treatment of EC, without need to hysterectomy or histological diagnosis. [ABSTRACT FROM AUTHOR]

The association between immunoregulatory cytokines, such as interleukin (IL)‐10 or IL‐35, and dipeptidyl peptidase‐4 inhibitor (DPP4i)‐related bullous pemphigoid (BP) has not been evaluated. Serum IL‐10 and IL‐35 levels were measured in 39 patients with BP (24 males and 15 females; 6 DPP4i‐related and 33 DPP4i‐unrelated BP patients) and 10 healthy controls. The number of CD26+ cells in the dermis around bulla on sections was counted immunohistochemically for 12 patients (six patients with DPP4i‐related BP and six randomly sampled patients with DPP4i‐unrelated BP). Patients with DPP4i‐related BP had lower levels of serum eosinophils (DPP4i‐related vs. DPP4i‐unrelated BP: 476.1 ± 234.0 vs. 911.3 ± 948.8/μL; p = 0.537) and a higher rate of infiltrating CD26+ cells (32.9 ± 7.1% vs. 15.7 ± 4.4%; p = 0.01). There were no significant differences in serum IL‐10 (6.77 ± 0.24 vs. 6.84 ± 0.20 pg/mL), serum IL‐35 (2.63 ± 0.17 vs. 2.63 ± 0.21 pg/mL), serum anti‐BP180NC16a antibodies (67.31 ± 37.4 vs. 76.18 ± 54.59 U/mL) and Bullous Pemphigoid Disease Area Index before treatment in this study. Serum IL‐10 and IL‐35 levels do not increase in patients with BP and may not be a candidate for a therapeutic target for BP. An increase in CD26+ cells might be associated with DPP4i‐related BP. [ABSTRACT FROM AUTHOR]

Background: Knowing which patients would be more likely to die is crucial for making better use of the little resources available. To do this, the ability of several inflammatory indicators to identify mortality outcomes has been detected. Materials and methods: A total of 125 severe/critical COVID-19 patients were involved in this work divided into two groups based on survival, dead group (62 patients) and live group (63 patients). Between March 2022 and July 2022, these patients were admitted to Marjan medical city and Al-Sadeq hospital. Patients were determined as severe cases according to the guidelines released by National Health World. The inflammatory cytokine (IL-35) was detected by the ELISA technique. Results: IL-35 showed no statistical differences between lived 6.85 (5.44-8.72) ng/ml and dead 6.53 (5.82-7.89) ng/ml patients (p= 0.79). D dimer, and ferritin increased significantly in dead patients 2467.5 (1368. 7-3697) ng/ml and 1621.5 (792.3-2359) ng/ml respectively compared to live patients 557 (430-689) ng/ml and 268 (186-449) ng/ml respectively (P < 0.0001). The ROC or area under the curve (AUC) for D-dimer was 0.89 with high sensitivity (95%) and specificity (77%). Ferritin also showed a large AUC that was 0.90 with high sensitivity and specificity (95%) and (81%) respectively. The cut off point for both D-dimer and ferritin was 693.67 ng/ml and 475 ng/ml respectively. Conclusions: IL-35 revealed no significant differences between dead and lived patients with COVID-19 (p = 79). Positive strong correlation observed between ferritin and D-dimer (r= 0.85, p< 0.0001). No correlation was found between IL-35 and both ferritin and D-dimer (p > 0.05). [ABSTRACT FROM AUTHOR]

Purpose: Recent emergence of miRNAs as important regulators of processes involving lesion formation and regression has highlighted miRNAs as potent therapeutic targets for the treatment of atherosclerosis. Few studies have reported the atheroprotective role of IL-35, a novel immunosuppressive and anti-inflammatory cytokine; however, miRNA-dependent regulation underlying the anti-atherosclerotic potential of IL-35 remains elusive. Methods: THP-1 macrophages were incubated with human recombinant IL-35 (rIL-35) either in the presence or absence of ox-LDL. qRT-PCR was conducted to validate the expression levels of previously identified miRNAs including miR-197-5p, miR-4442, miR-324-3p, miR-6879-5p, and miR-6069 that were differentially expressed in peripheral blood mononuclear cells of coronary artery disease (CAD) patients vs. controls. Additionally, bioinformatic analysis was performed to predict miRNA-associated targets and their corresponding functional significance in CAD. Results: Exogenous IL-35 significantly decreased the average area of ox-LDL-stimulated macrophages, indicating the inhibitory effect of IL-35 on lipid-laden foam cell formation. Furthermore, rIL-35 treatment alleviated the ox-LDL-mediated atherogenic effects by modulating the expression levels of aforementioned CAD-associated miRNAs in the cultured macrophages. Moreover, functional enrichment analysis of these miRNA-related targets revealed their role in the molecular processes affecting different stages of atheroslerotic plaque development, such as macrophage polarization, T cell suppression, lipoprotein metabolism, foam cell formation, and iNOS-mediated inflammation. Conclusion: Our observations uncover the novel role of IL-35 as an epigenetic modifier as it influences the expression level of miRNAs implicated in the pathogenesis of atherosclerosis. Thus, IL-35 cytokine therapy–mediated miRNA targeting could be an effective therapeutic strategy against the development of early atheromas in asymptomatic high-risk CAD patients. [ABSTRACT FROM AUTHOR]

Objective: Chronic spontaneous urticaria (CSU) has a profound impact on the sleep quality, productivity and overall quality of life of affected individuals. This study aimed to investigate the correlation between serum Th17/Treg immune dysregulation and the severity of CSU in patients. Methods: Clinical baseline data of 120 CSU patients and matched healthy controls were recorded. The pruritus level, disease severity, and quality of life of CSU patients were assessed using the visual analogue scale, weekly Urticaria Activity Score and chronic urticaria quality of life questionnaire, respectively. The Th17/Treg cell ratio was detected by flow cytometry. ELISA was used to measure the levels of serum Th17 cytokines (IL‐17, IL‐21) and Treg cytokines (TGF‐β1, IL‐35). Pearson's correlation analysis was conducted to examine the associations between these indicators. Results: No significant differences were identified in terms of sex, age, and BMI between the two groups. However, CSU patients exhibited a significant increase in the Th17 cell ratio, as well as the elevated serum levels of TGF‐β1, IL‐17 and, IL‐21. Conversely, the proportion of Treg cells and the levels of IL‐35 were remarkably decreased in CSU patients. Peripheral blood Th17 cells were negatively correlated with Treg cells. The severity of pruritus, life quality, and disease severity in CSU patients were positively correlated to Th17 cell ratio, and inversely correlated with Treg cell proportion. Conclusions: A positive correlation was found between the percentage of peripheral blood Th17 cell in CSU patients and the pruritus level, life quality, and disease severity. In constrast, there was a negative correlation between the proportion of peripheral blood Treg cells and these clinical parameters. [ABSTRACT FROM AUTHOR]

In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can lead to inflammation in the brain and periphery. The novel cytokine interleukin (IL)-35 has described anti-inflammatory properties; however, the plasma levels of IL-35 in children with ASD have never been investigated. The plasma levels of IL-35 were measured by an enzyme-linked immunosorbent assay in 30 children with ASD and 39 typically developing (TD) controls. In the current study, we found that plasma IL-35 levels were significantly decreased in children with ASD compared with TD children. Furthermore, lower IL-35 levels were associated with worse behaviors as assessed using the aberrant behavior checklist. These findings are in line with other observations of decreased regulatory cytokines such as transforming growth factor beta and IL-10 in ASD, and associations with severity of behaviors. In conclusion, regulating the expression of IL-35 may provide a new possible target for the treatment of immune issues in ASD to address an imbalance between pro- and anti-inflammatory signals that alter the behavioral phenotype.

The host response to helminth infections is characterized by systemic and tissue-related immune responses that play a crucial role in pathological diseases. Recently, experimental studies have highlighted the role of regulatory T (Tregs) and B (Bregs) cells with secreted cytokines as important markers in anti-schistosomiasis immunity. We investigated the serical levels of five cytokines (TNFα, IFN-γ, IL-4, IL-10 and IL-35) in pre- and post-treatment samples from chronic Schistosoma infected patients to identify potential serological markers during follow-up therapy. Interestingly, we highlighted an increased serum level of IL-35 in the pre-therapy samples (median 439 pg/mL for Schistosoma haematobium and 100.5 pg/mL for Schistsoma mansoni infected patients) compared to a control group (median 62 pg/mL and 58 pg/mL, respectively, p ≤ 0.05), and a significantly lower concentration in post-therapy samples (181 pg/mL for S. haematobium and 49.5 pg/mL for S. mansoni infected patients, p ≤ 0.05). The present study suggests the possible role of IL-35 as a novel serological biomarker in the evaluation of Schistosoma therapy follow-up. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF‐β and IL‐35, a recently identified heterodimeric cytokine that belongs to the IL‐12 cytokine family. However, the effect of regulatory IL‐35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL‐35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL‐35 and different profibrotic cytokines in fibrotic (F‐ILD) and non‐fibrotic (NF‐ILD) patients by ELISA were compared to that of intracellular IL‐35 and IL‐17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL‐35 (rIL‐35) and TGF‐β (rTGF‐β), which were evaluated by flow cytometry. We observed that BAL concentration of IL‐35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF‐β (p < 0.001) and IL‐17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL‐35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL‐17 + CD4+ T cells (p < 0.001). The percentage of IL‐35 + CD4+ T cells correlated positively with BAL concentration of IL‐35 (p = 0.02), but correlated negatively with BAL concentrations of IL‐17 (p = 0.007) and TGF‐β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF‐β: IL‐35 ratio of 1:4, an enhanced percentage of IL‐35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL‐17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL‐35 to the BAL from F patients until a 1:4 ratio of TGF‐β: IL‐35 was reached, a significantly increased percentage of IL‐35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL‐17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL‐35 may induce an anti‐fibrotic response, regulating the effect of TGF‐β and the inflammatory response on CD4+ T cells. In addition, the TGF‐β: IL‐35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD. [ABSTRACT FROM AUTHOR]

Brucellosis is significantly influenced by the interactions between the causative Brucella bacteria and host immunity. Recently identified cytokines have been described for their immunomodulatory effects in numerous inflammatory, autoimmune and infectious diseases. Some of them are new members of cytokine superfamilies, including several members of the IL-12 superfamily (IL-35, IL-39). The major purpose of the present study was to investigate the role of these new immunomodulatory cytokines in Brucella infections. The levels of IL-35 and IL-39 in the serum of 40 acute and 40 chronic brucellosis patients and 40 healthy controls were measured by ELISA. The mRNA levels of IL-35 and IL-39 in PBMCs were detected by RT-qPCR. Both IL-35 and IL-39 serum concentrations were significantly higher in healthy control subjects than in brucellosis patients, and IL-35 and IL-39 serum levels of chronic brucellosis patients were higher than those of acute cases. It was also found that the expression of Ebi3/IL-12A (IL-35 genes) and Ebi3/IL-23A (IL-39 genes) was upregulated in chronic brucellosis patients compared to healthy controls. Moreover, the expression of the Ebi3/IL-12A and Ebi3/IL-23A genes was lower in patients with acute brucellosis than in patients with chronic brucellosis. Overall, this study showed that IL-35 and IL-39 are positively correlated in brucellosis and significantly decreased during the disease. Significantly lower levels of IL-35 and IL-39 in acute brucellosis than in chronic brucellosis and healthy controls suggest that these cytokines may play a key role in suppressing the immune response to brucellosis and its progression to chronicity. IL-35 and IL-39, new members of the IL-12 cytokine family, are immunomodulatory cytokines characterized as anti-inflammatory and pro-inflammatory, respectively. In acute and chronic brucellosis, serum IL-35 and IL-39 are significantly decreased. In acute brucellosis, serum IL-35 are significantly lower than in chronic brucellosis, suggesting that this cytokine may play a role in chronification. A positive correlation was found between IL-35 and IL-39 in acute and chronic brucellosis, suggesting that the common protein subunit Ebi may be suppressed. According to the results of this study, IL-35 and IL-39 may play a role in the pathogenesis of brucellosis. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) and ulcerative colitis (UC) are two chronic relapsing inflammatory bowel diseases (IBD). Although there are several treatment options available to improve the symptoms of IBD patients, there is no effective treatment that provides a definitive solution. In the present study, we aim to investigate the antioxidative/anti-inflammatory effects of oral administration of boric acid and Bacillus clausii in a rat trinitrobenzenesulfonic acid (TNBS)-induced colitis model. The effects of boric acid and B. clausii were examined in serum and colon tissues with the help of some biochemical and histological analyses. Elevated inflammation and oxidative damage were found in the blood and colon tissue samples in the TNBS-induced group according to the complete blood count (CBC), tumor necrosis factor (TNF) alpha, interleukin-35 (IL-35), malondialdehyde (MDA), glutathione peroxidase (GPx), myeloperoxidase (MPO), nitric oxide (NO), and histological findings. Particularly, the highest IL-35 level (70.09 ± 12.62 ng/mL) in the combined treatment group, highest catalase activity (5322 ± 668.1 U/mg protein) in the TNBS-induced group, and lower relative expression of inducible nitric oxide synthase in the TNBS-induced group than the control group were striking findings. According to our results, it can be concluded that boric acid showed more curative effects, even if B. clausii probiotics was partially ameliorative. [ABSTRACT FROM AUTHOR]

IgG4-related disease (RD) is a proposed concept of systemic inflammatory condition from Japanese researchers. Patients with IgG4-RD manifest several immunological and histological characterizations in the organs involved, including elevated levels of serum IgG4 and lympho-plasmacytic infiltration, storiform fibrosis, IgG4-positive plasma cells infiltration, and obstructive phlebitis. Nevertheless, the pathogenesis of IgG4-RD still remains unclear. It has been made clear that several immune cells with regulatory function play a vital part in several diseases. In particular, abnormalities in the function and proportion of regulatory T cells (Tregs) are implicated in several diseases, and their part in IgG4-RD has been investigated. This review offers an overview of the research in IgG4-RD related to Tregs. Herein, the basic information of Tregs, knowledge gained from animal models involving Tregs, and the role of IgG4-RD has been provided. We also included the immunological mechanisms of IgG4-RD based on the data accumulated so far in our hypothesis.

Abstract Background Cancer‐related cachexia is a major cause of treatment resistance and poor prognosis, which is characterized by anorexia and skeletal muscle depletion. To date, there have been no reports on the relationship between IL‐35 and cancer‐related cachexia in patients with stage IV non‐small cell lung cancer. Methods Serum IL‐35 levels in 86 patients with stage IV NSCLC were measured and statistically analyzed based on patients' clinicopathological parameters. Serum albumin levels, C‐reactive protein, and skeletal muscle index (SMI) of the patients were also determined. In vivo studies using a mouse model were also conducted by subcutaneously injecting immunodeficiency (SCID) mice with overexpressing IL‐35 cell lines and determining their daily food intake, bodyweight and muscle atrophy. Cachexia indicators were measured again after administering the mice with an anti‐IL35 neutralizing antibody. Results Patients with stage IV NSCLC had significantly higher serum IL‐35 levels than the healthy controls. Similarly, circulating IL‐35 levels were significantly higher in patients with cachexia than those without. The SMI values of patients with high serum IL‐35 levels were significantly lower than those with low serum IL‐35 levels. Mice subcutaneously injected with LLC PLV‐IL‐35 cell lines exhibited anorexia, weight loss, and muscle atrophy. Moreover, these symptoms were significantly reduced after administering the mice with an anti‐IL35 neutralizing antibody. Conclusions This study reveals that high serum IL‐35 expression is associated with non‐small cell lung cancer cachexia and skeletal muscle atrophy. These findings highlight its potential as a biomarker and therapeutic target for controlling cachexia of advanced lung cancer.

This study aimed to investigate the relationship between interleukin (IL)-35 level and IL-35-producing regulatory T cells (iTr35 subset) in Mycobacterium tuberculosis (Mtb)-infected mice. After the mice were injected with Mtb strain H37R via tail vein, the bacterial burden, lung lesions, and the impact of immune suppression on the infected mice were respectively assessed. The results, when compared with the control mice, showed that the mRNA expression levels of the p35 and Epstein-Barr virus-induced gene 3 of IL-35 were significantly increased in the Mtb-infected mouse spleen at 4 or 8 weeks post-infection and their protein expression levels were concurrently increased in the lungs of the mice, especially in 8 week infected mice. In addition, the levels of serum IL-35 and the iTr35 subset in the spleen of mice were also increased in 4 or 8 weeks post-infection compared with the control mice. Importantly, the high bacterial burden and lung lesions and the low mouse weight were found at 8 week post-infection. Therefore, the mice infected with Mtb resulted in elevating IL-35 level and iTr35 subset and increasing bacterial burden and lung lesions. The findings from the study suggest IL-35 and iTr35 cells may exert an immune suppression role in chronic Mtb-infected mice.

巨噬细胞具有极强的异质性，在不同微环境刺激下可发生 M1/M2 型极化。巨噬细胞 M1/M2 表型在创面愈合中分 别发挥促进炎症和修复的作用。而 IL-35 对巨噬细胞 M1/M2 型极化有重要影响。笔者旨在总结 IL-35 对巨噬细胞 M1/M2 型极 化以及炎症反应的影响，认为 IL-35 对创面愈合具有促进作用，以期为促进创面愈合的临床治疗提供新的治疗策略。 [ABSTRACT FROM AUTHOR]

Cardiovascular disease represents a complex series of clinical syndromes with multiple aetiologies. Cardiovascular diseases have become one of the most common causes of death among middle‐aged and elderly people worldwide because of their diverse types and wide range of patients. With the development of research in this field, increasing evidence shows that cytokines remain important to address in the beginning, progression and outcome of cardiovascular diseases. The interleukin (IL)‐12 family, which includes IL‐12, IL‐23, IL‐27 and IL‐35, is an important family of cytokines that plays roles in the regulation of chronic inflammation, tumour progression, autoimmune disease and cardiovascular disease. IL‐12 family members have distinct pro‐inflammatory and anti‐inflammatory effects and affect the progression of cardiovascular disease all the time. In particular, the novel member of this family IL‐35 has turned out to play a major part in the occurrence and development of various cardiovascular diseases such as atherosclerosis, acute coronary syndrome, myocardial infarction and viral myocarditis. In this review, the source, structure, receptor, signal transduction and biological functions of IL‐35 are summarized with a focus on the relationship with cardiovascular disease. We further discuss the molecular and cellular mechanisms that may be involved in these effects to guide the development of new strategies targeting IL‐35 for the prevention and clinical treatment of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Objective: The objective of the current study was to examine the changes in the serum level of some immunological markers in Graves' disease (GD) patients in comparison to healthy controls. In order to evaluate its utility as clinical biomarker of autoimmune disorder as well as to establish the changes of some immunological markers and clinical outcome that is associated with radioactive iodine treatment. Methodology: Serum levels of interleukin-35 (IL-35), anti-TSHR antibody and human insulin-like growth factor 1 (IGF-1) were measured using ELISA assay. The blood samples were collected from a total of 70 Iraqi GD patients who were enrolled in this study during the period between February and April 2022. They were divided into two groups: The first group involved 35 patients with GD without treatment and the second group involved 35 patients who received radioactive iodine therapy (RAI). In addition, 30 people apparently healthy worked as control group. Results: The results showed a significant decrease in serum levels of IL-35 and anti-TSHR in untreated and treated GD patients as compared to healthy control. The data also revealed that serum level of IGF-1 was higher in untreated GD patients compared to the control group, but it was decreased in treated GD patients. Also, there were a difference at serum levels of IL-35 and TSH-R when compared between the untreated and treated GD patients. Conclusions: The results of IL-35 and anti-TSHR, and IGF-1 levels in the serum of the studied groups suggests the potential anti-inflammatory function of these biomarkers in GD. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the relationship between immunological markers and the dysfunction of cutaneous microcirculation in young patients with type 1 diabetes. The study group consisted of 46 young patients with type 1 diabetes and no associated complications. Microvascular function was assessed with the use of nail fold capillaroscopy before and after implementing post-occlusive reactive hyperemia. This evaluation was then repeated after 12 months. Patients were divided into two subgroups according to their baseline median coverage (defined as the ratio of capillary surface area to surface area of the image area), which was established during the initial exam (coverageBASE). Additionally, the levels of several serum biomarkers, including VEGF, TNF-a and IL-35, were assessed at the time of the initial examination. HbA1c levels obtained at baseline and after a 12-month interval were also obtained. Mean HbA1c levels obtained during the first two years of the course of the disease were also analyzed. Patients with coverageBASE below 16.85% were found to have higher levels of VEGF and TNF-α, as well as higher levels of HbA1c during the first two years following diabetes diagnosis. Our results support the hypothesis that the development of diabetic complications is strongly influenced by metabolic memory and an imbalance of pro- and anti-inflammatory cytokines, regardless of achieving adequate glycemic control.

Breast cancer is still a major concern due to its relatively poor prognosis in women, although there are many approaches being developed for the management of breast cancer. Extensive studies demonstrate that the development of breast cancer is determined by pro versus anti tumorigenesis factors, which are closely related to host immunity. IL-35 and IL-37, anti-inflammatory cytokines, play an important role in the maintenance of immune homeostasis. The current review focuses on the correlation between clinical presentations and the expression of IL-35 and IL-37, as well as the potential underlying mechanism during the development of breast cancer in vitro and in vivo. IL-35 is inversely correlated the differentiation and prognosis in breast cancer patients; whereas IL-37 shows dual roles during the development of breast cancer, and may be breast cancer stage dependent. Such information might be useful for both basic scientists and medical practitioners in the management of breast cancer patients. [ABSTRACT FROM AUTHOR]

Background and objective: Host immunity is crucial during periodontal inflammations. B cells are considered to have a function of immunoregulation, and TLRs are considered to be crucial in this process. The present study illustrates the potential roles and rules of CD25+ B cells during periodontitis, especially its effect on regulating host IL‐35 level and Th1, Th17, and Treg differentiation. Material and methods: The proportion of local and systemic CD25+ B cell subpopulations from periodontitis models were identified by flow cytometry. To illustrate further mechanism, B cells were cultured with a different type of TLR activators. Expression of IL‐10, IL‐35, and TGF‐β was detected by ELISA and real‐time PCR. We also set adoptive transfer models by using CD25+ B cells. Alveolar bone erosion, proportion of Th1, Th17, and Tregs, and levels of IFN‐γ, TNF‐α, IL‐1β, and IL‐17 were identified. Result: Periodontitis induces more CD25+ B cell subpopulations and promotes their IL‐10, IL‐35, and TGF‐βproduction. TLR activators enhanced Breg proliferation and function. LPS+CpG obviously induced more CD25+ B cell differentiation and production of IL‐10, IL‐35, and TGF‐β. Adoptive transfer of CD25+ B cells reduces alveolar bone destruction and local Tregs, proportion, especially the local level of IFN‐γ and IL‐17. In addition, adoptive transfer of CD25+ B cells remedies the pathological change in the proportion of IL‐1β and Th1/Th17 in local lesions. We did not find any significant difference in peripheral blood, regardless of group and detected items. Conclusion: Results of the present study clarify that CD25+ B cells enlarged and produced more IL‐10, IL‐35 and TGF‐β during periodontitis, activation of TLR4 and TLR9 played crucial roles in this process. Also, CD25+ B cells alleviated periodontal inflammation and alveolar bone resorption. Our findings further expanded the potential of B cells during periodontitis. [ABSTRACT FROM AUTHOR]

Background: A case-control study examined the relationship between bacterial prostatitis and IL-35 blood levels in the emergence of male infertility. Objective: This study aimed to assess the role that bacterial prostatitis and IL-35 play in the progression of male infertility in patients from Najaf province. Patients and Procedures: 120 patients were seen at AL-Sadder Medical City, Al-Najaf province through the period from January to June, 2021. This number included sixty prostatitis-related infertile patients, 30 prostatitis-related fertile patients, and 30 infertile patients. 30 healthy fertile male subjects served as control group. All subjects provided blood and semen samples and three ml of the blood were placed in a gel tube to separate the serum used to calculate IL-35 level by ELISA. A loop of semen was collected to identify the bacterial culprits as well as semen liquefaction, volume, appearance, and fundamental sperm characteristics in the residual semen (density, motility, viability, and morphology). Results: Prostatitis patients had considerably lower serum concentrations of IL-35 than infertile patients did, according to the findings (P< 0.05). The concentration of IL-35, which is thought of as a biomarker for a progressive state, decreased with the severity of the disease. The findings showed that S. aureus and E. coli were the most frequent bacterial causes of prostatitis. Conclusion: The current study found a correlation between infertility and the infection with prostatitis condition, which is reflected in the body's immune response as a lower level of IL-35. [ABSTRACT FROM AUTHOR]

Bone marrow-derived mesenchymal stem cells (BMSCs) have been widely studied for their applications in immunoregulation and tissue repair. However, the therapeutic effects of BMSCs in the body are limited, partly due to the low homing efficiency of BMSCs to affected parts. The stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis is well known to play an essential role in the homing of BMSCs. Interleukin 35 (IL-35) is a newly discovered cytokine confirmed to inhibit overactivated immune function and have a good therapeutic effect on autoimmune diseases. In this study, we innovatively developed dual gene modification of BMSCs by transducing CXCR4 and IL-35 and found that the migration and immunomodulatory activity of genetically engineered BMSCs were significantly enhanced compared to their natural counterparts. These results suggest that BMSCs modified by dual overexpression of CXCR4 and IL-35 may provide a potential treatment strategy for autoimmune diseases. [Display omitted] • CXCR4 overexpression promotes migration of BMSCs to SDF-1. • CXCR4-dependent homing efficiency due to reduction of E-cadherin and promotion of N-cadherin and vimentin proteins in BMSCs. • IL-35 overexpression enhances the immunosuppressive function of BMSCs. • Dual CXCR4/IL-35 overexpression promotes BMSCS migration and immunosuppression. [ABSTRACT FROM AUTHOR]

Giardia lamblia, Entamoeba histolytica, Cryptosporidium, and Blastocystis are some parasites primarily responsible for human infections. Giardia lamblia, also known as Giardia intestinalis or Giardia duodenalis, is a common pathogenic protozoan found in the human duodenum and jejunum that causes giardiasis. This study collected stool and blood samples from patients with diarrhea aged less than 1 month to 15 years, from September 2020 to December 2020, in Thi-Qar province. Our study aimed to reveal the diagnosis of Giardia lamblia using direct microscopy examination and detect some immunological parameters such as IL-17 and IL-35 in patients infected with giardiasis. [ABSTRACT FROM AUTHOR]

Abstract Background IL-35 subunit EBI3 is up-regulated in pulmonary fibrosis tissues. In this study, we investigated the pathological role of EBI3 in pulmonary fibrosis and dissected the underlying molecular mechanism. Methods Bleomycin-induced pulmonary fibrosis mouse model was established, and samples were performed gene expression analyses through RNAseq, qRT-PCR and Western blot. Wild type and EBI3 knockout mice were exposed to bleomycin to investigate the pathological role of IL-35, via lung function and gene expression analyses. Primary lung epithelial cells were used to dissect the regulatory mechanism of EBI3 on STAT1/STAT4 and STAT3. Results IL-35 was elevated in both human and mouse with pulmonary fibrosis. EBI3 knockdown aggravated the symptoms of pulmonary fibrosis in mice. EBI3 deficiency enhanced the expressions of fibrotic and extracellular matrix-associated genes. Mechanistically, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process. Conclusion IL-35 might be one of the potential therapeutic targets for bleomycin-induced pulmonary fibrosis.

Background: Cytokines have an essential contribution to the inflammatory response and the development of chronic inflammation. Therefore, it has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). Interleukins are closely related to RA, and the exact role of some interleukins in the pathogenesis of RA is not yet known. Objectives: To evaluate the levels of interleukins and their ratio, since the levels of interleukins 35 and 39 in RA patients have not yet been determined in Iraq. Patients and methods: An ELISA (enzyme-linked immunosorbent assay) was used to measure the levels of interleukins in the blood of 56 patients with RA and 44 healthy volunteers who were enrolled in the study from November 2021 to March 2022. Results: The serum levels of IL-39 in the RA patient groups were significantly higher than in the control groups (p = 0.043). In contrast, the level of IL-35 was slightly higher in RA patients but not by significantly different values (p = 0.055). The cytokine ratio, IL-39/IL-35, was the same for the groups, and there were no significant differences when comparing patients to controls (14.30 ± 1.47 vs. 13.18 ± 0.71). In addition, IL-39 concentration levels were significantly higher in RA patients under therapy than in RA patients with a first diagnosis and without therapy. Conclusion: The study concluded the crucial role of pro-inflammatory and anti-inflammatory cytokines in the progression of RA.

Background: Immune Thrombocytopenic Purpura (ITP) is one of the common autoimmune diseases in Egypt, this disease causes a considerable drop in platelet counts rendering the patients at very high risk of bleeding. For this, ongoing research to determine an accurate diagnostic tool that would help in rapid diagnosis and also the remote prognosis of the disease are continuous. IL-35 is one of the interleukin family that now has been highlighted as a useful prognostic marker in many autoimmune diseases e.g.: SLE. In the light of its significance that was detected in other autoimmune disease, this study was to specify this interleukin in the context of the diagnosis of ITP. Method: This pilot observational study was carried out on 60 patients and 20 normal controls. The patient group was categorized into newly diagnosed, relapsed and resistant groups. IL-35 was measured in serum by ELISA. Results: This study demonstrated that plasma IL-35 levels were significantly lower in ITP patients than those in healthy controls and that IL-35 expression levels positively correlated with circulating platelet counts. Moreover, it was noted that a decrease in IL-35 contributes to the pathogenesis of ITP, and a statistically significant association between IL-35 levels and disease outcomes in ITP patients (P = 0.033). Specifically, patients with elevated IL-35 levels exhibited higher remission rates (28.8%) than patients experiencing only partial remission or resistance to treatment. Conclusion: This finding suggested that IL-35 may play a role in predicting or potentially influencing disease prognosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • T1DM has characteristics marked with a gradual immune-mediated deterioration of the β-cells producing insulin. • IL-35 has potential role as an effective autoimmune inhibitor and has potential therapeutic value in T1DM clinical trials. • Administration of IL-35, could block effector Th1 and Th17 and has a positive feedback effect. • IL-35 boosting Treg, IL-35-producing iTreg35, and IL-35-producing iBreg35 expansion. A chronic autoimmune condition known as type 1 diabetes mellitus (T1DM) has characteristics marked by a gradual immune-mediated deterioration of the β-cells that produce insulin and causes overt hyperglycemia. it affects more than 1.2 million kids and teenagers (0–19 years old). In both, the initiation and elimination phases of T1DM, cytokine-mediated immunity is crucial in controlling inflammation. T regulatory (Treg) cells, a crucial anti-inflammatory CD4+ T cell subset, secretes interleukin-35 (IL-35). The IL-35 has immunomodulatory properties by inhibiting pro-inflammatory cells and cytokines, increasing the secretion of interleukin-10 (IL-10) as well as transforming Growth Factor- β (TGF-β), along with stimulating the Treg and B regulatory (Breg) cells. IL-35, it is a possible target for cutting-edge therapies for cancers, inflammatory, infectious, and autoimmune diseases, including TIDM. Unanswered questions surround IL-35's function in T1DM. Increasing data suggests Treg cells play a crucial role in avoiding autoimmune T1DM. Throughout this review, we will explain the biological impacts of IL-35 and highlight the most recently progresses in the roles of IL-35 in treatment of T1DM; the knowledge gathered from these findings might lead to the development of new T1DM treatments. This review demonstrates the potential of IL-35 as an effective autoimmune diabetes inhibitor and points to its potential therapeutic value in T1DM clinical trials. [ABSTRACT FROM AUTHOR]

[Display omitted] • IL-35 can offer protection against type-1 diabetes mellitus (T1DM) and autoimmune diabetes mellitus (AIDM). • IL-35 regulates macrophage polarization, T-cell-related cytokines, and regulatory B cells (Bregs). • The analysis of advanced protein/enzymatic markers in diabetes revealed the potential role of IL-35-mediated immunotherapy in treating T1DM and AIDM. IL-35 is a recently discovered protein made up of IL-12α and IL-27β chains. It is encoded by IL12A and EBI3 genes. Interest in researching IL-35 has significantly increased in recent years, as evidenced by numerous scientific publications. Diabetes is on the rise globally, causing more illness and death in developing countries. The International Diabetes Federation (IDF) reports that diabetes is increasingly affecting children and teenagers, with varying rates across different regions. Therefore, scientists seek new diabetes treatments despite the growth of drug research. Recent research aims to emphasize IL-35 as a critical regulator of diabetes, especially type 1 and autoimmune diabetes. This review provides an overview of recent research on IL-35 and its link to diabetes and its associated complications. Studies suggest that IL-35 can offer protection against type-1 diabetes and autoimmune diabetes by regulating macrophage polarization, T-cell-related cytokines, and regulatory B cells (Bregs). This review will hopefully assist biomedical scientists in exploring the potential role of IL-35-mediated immunotherapy in treating diabetes. However, further research is necessary to determine the exact mechanism and plan clinical trials. [ABSTRACT FROM AUTHOR]

Heart transplantation has become the only 'cure' for end‐stage heart diseases, but acute allograft rejection is the major obstacle to the survival of patients. Our previous studies showed that IL‐35 gene‐modified adipose‐derived mesenchymal stem cells (IL‐35‐ASCs) can effectively inhibit graft rejection and prolong the survival of transplanted hearts in mice. This study further explored the mechanism of IL‐35‐ASCs, especially focusing on the important role of IL‐35‐ASC‐derived exosomes (IL‐35‐ASCexos) in inhibiting acute rejection. IL‐35‐ASCs were constructed in vitro and pretreated with IL‐35 neutralizing antibody and GW4869 (an inhibitor of neutral sphingomyelinase that impairs exosome biogenesis/release). Then, pretreated IL‐35‐ASCs and CD4+ T cells were cocultured in Transwell plates, and changes in regulatory T cells (Tregs) and cytokines were detected. Then, IL‐35‐ASCexos were extracted, identified and analysed, and their immunoregulatory effects on CD4+ T cells were studied through coculture experiments. Finally, IL‐35‐ASCexos were applied to a mouse heart transplantation model to investigate the therapeutic effects on acute rejection of the allograft. The coculture experiment showed that the IL‐35‐neutralizing antibody could not completely block the immunosuppressive function of IL‐35‐ASCs, while GW4869 could effectively reduce their immunoregulatory characteristics. Similar to IL‐35‐ASCs, IL‐35‐ASCexos also have powerful immunosuppressive properties, effectively upregulating the Treg ratio in vivo and in vitro and prolonging graft survival. As the main effectors of IL‐35‐ASCs, these findings highlight the therapeutic potential of IL‐35‐ASCexos in inhibiting acute cardiac rejection of the allograft. Although the specific mechanism remains unclear and needs to be further explored, IL‐35‐ASCexos therapy is expected to become a new method to inhibit acute graft rejection. [ABSTRACT FROM AUTHOR]

Objective: As a member of interleukin-12 family, interleukin-35 (IL-35) plays an important regulatory role in immune response. The relationship between IL-35 and idiopathic membranous nephropathy (IMN) is still unclear, and the purpose of this study is to clarify the relationship between IL-35 and disease activity and remission of IMN. Methods: This study was a single-center, retrospective study in which all patients were diagnosed with IMN by renal biopsy or aPLA2R titer and treated with Mahuang Fuzi and Shenzhuo Decoction (MFSD). A follow-up was conducted with the endpoint of clinical complete or partial remission (CR + PR). Levels of serum IL-35 were measured and its relationship with IMN remission were analyzed. The regulatory T cell (Treg) and inducible IL-35 producing Tregs (iTR35) in peripheral blood of IMN patients were detected by flow cytometry. Results: A total of 76 IMN patients (age 51.95 ± 13.29) were followed-up for 18 (12, 24) months. The level of serum IL-35 in all patients increased after treatment, but the degree of increase in remission group was significantly higher than that in no remission (NR) group (117.6% vs 83.7%, P<0.01). The baseline IL-35 level in remission group was higher than that in NR group (174.87 vs.151.87 pg/ml, P=0.016). Cox regression analysis showed that baseline IL-35 level was a independent risk factor for IMN remission (HR 1.081, 95%CI 1.048-1.116, P<0.001). Patients with baseline IL-35 lower than the lower quartile (<145.49 pg/ml) had an average remission time twice as long as those with baseline IL-35 higher than the upper quartile (> 203.05 pg/ml) (12mon vs. 24mon, P<0.01). The baseline IL-35 can predict the remission time of IMN patients with either aPLA2R positive (AUC=0.673) or negative (AUC=0.745). Analysis of 18 patients with IMN showed that IL-35 level had a higher correlation with iTR35, but not Treg (r=0.613, P<0.05). Conclusions: The level of IL-35 in patients with IMN showed an increasing trend with the progress of treatment, and the baseline IL-35 could predict the remission time of IMN patients, including those patients with negative aPLA2R. The level of IL-35 is related to the number of iTR35 cells. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in the early development of type 1 diabetes (T1D). Based on the phenotype, macrophages can be classified into pro-inflammatory (M1) and anti-inflammatory (M2) macrophages. Despite intensive research in the field of macrophages and T1D, the kinetic response of M1/M2 ratio has not been studied in T1D. Thus, herein, we studied the M1 and M2 macrophages in the early development of T1D using the multiple low dose streptozotocin (MLDSTZ) mouse model. We determined the proportions of M1 and M2 macrophages in thymic glands, pancreatic lymph nodes and spleens on days 3, 7 and 10 after the first injection of STZ. In addition, we investigated the effect of IL-35 in vivo on the M1/M2 ratio and IL-35+ plasmacytoid dendritic cells in diabetic mice and in vitro on the sorted macrophages. Our results revealed that the M1/M2 ratio is higher in STZ-treated mice but this was lowered upon the treatment with IL-35. Furthermore, IL-35 treated mice had lower blood glucose levels and a higher proportion of IL-35+ cells among pDCs. Macrophages treated with IL-35 in vitro also had a higher proportion of M2 macrophages. Together, our data indicate that, under diabetic conditions, pro-inflammatory macrophages increased, but IL-35 treatment decreased the pro-inflammatory macrophages and increased anti-inflammatory macrophages, further suggesting that IL-35 prevents hyperglycemia by maintaining the anti-inflammatory phenotype of macrophages and other immune cells. Thus, IL-35 should be further investigated for the treatment of T1D and other autoimmune disorders. [ABSTRACT FROM AUTHOR]

As an indispensable process for breast cancer metastasis, tumour angiogenesis requires a tight interaction between cancer cells and endothelial cells in tumour microenvironment. Here, we explored the participation of small extracellular vesicles (sEVs) derived from breast cancer cells in modulating angiogenesis and investigated the effect of IL‐35 in facilitating this process. Firstly, we characterized breast cancer cells‐derived sEVs untreated or treated with IL‐35 and visualized the internalization of these sEVs by human umbilical vein endothelial cells (HUVECs). Breast cancer cells‐derived sEVs promoted endothelial cell proliferation through facilitating cell cycle progression and enhanced capillary‐like structures formation and microvessel formation. Subsequent results proved that IL‐35 further reinforced the angiogenic effect induced by breast cancer cells‐derived sEVs. Moreover, sEVs from breast cancer cells significantly enhanced tumour growth and microvessel density in breast tumour‐bearing mice model. Microarray analysis showed that IL‐35 might alter the mRNA profiles of sEVs and activate the Ras/Raf/MEK/ERK signalling pathway. These findings demonstrated that IL‐35 indirectly promoted angiogenesis in breast cancer through regulating the content of breast cancer cells‐derived sEVs, which could be internalized by HUVECs. [ABSTRACT FROM AUTHOR]

We investigated the role of rhIL-35, at low concentrations compatible with those produced by human trophoblast cells (less than 1 ng/mL), on human T helper (Th) cell functions and the presence of decidual IL-35-producing Th cells in human pregnancy. We found that human trophoblast cells produced IL-35 but not IL-4 or IL-10. RhIL-35, at concentrations produced by human trophoblasts, polarized T cells towards IL-35+, IL-10+, IL-4+ Th2-type cells and to Foxp3+ EBI3+ p35+ T reg cells producing IL-35 but not IL-10 and IL-4. Moreover, rhIL-35 at low concentrations did not suppress the proliferation of Th cells but stimulated IL-4 and IL-10 production by established Th clones. In particular, Th1-type clones acquired the capacity to produce IL-4. In addition, purified human trophoblast cell supernatants containing IL-35 upregulated IL-4 and IL-10 production by Th clones. Finally, IL-35+, IL-10+, IL-4+ Th2-type cells, which were found to be induced by low concentrations of IL-35 compatible with those produced by human trophoblasts, are exclusively present in the decidua of a successful pregnancy and at the embryo implantation site, suggesting their stringent dependence on trophoblast cells. Thus, the proximity of Th cells to IL-35-producing trophoblasts could be the determining factor for the differentiation of IL-35+, IL-10+, IL-4+ Th2-type cells that are crucial for human pregnancy success. [ABSTRACT FROM AUTHOR]