IL-35 has gained significant attention in recent years as a potential key regulator of diabetes, particularly chronic inflammatory type 1 and autoimmune diabetes, which are increasingly affecting children and teenagers across different regions worldwide [1-2]. 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) [3]. The development and progression of autoimmune diabetes or T1D can be influenced by various cytokines produced by both immune and pancreatic cells. Some cytokines, such as IL-10, TGF-β, IL-5, IL-4, IL-2, IL-15, IL-33, and IL-35, can stimulate regulatory cells in the immune system, leading to the release of anti-inflammatory cytokines such as IL-10 [4-5]. Regulatory dendritic cells release IL-7, which is particularly important for maintaining Tregs [4]. In T1D, Tregs selectively express IL-7Rα. Inhibition of TGF-β and activation of IFN-γ can increase the expression of TC, Th1, and Th17 cells, while TGF-β can stimulate Runx1 expression to convert Th1 cells into Th17 cells [4-5]
IL-35 is encoded by two separate genes called IL12A and Epstein–Barr virus-induced 3 (EBI3) [6]. Both the genes IL-12A and EBI3 are network with various disease as represented in figure 1. The data in the PubMed database indicated a direct correlation between IL-35 and EBI3 genes in many immune-inflammatory, autoimmune, cancer, and endocrine diseases [7]. Further from the PubMed database, we selected 10 protein/enzyme markers that have been clinically identified in relation to IL12A and EBI3. We then searched for their UniProt ID and human gene names in the UniProt databases and looked for their disease associations in the DisGeNET database v7.0. Gene-disease associations with N_PMIDs (citation) greater than or equal to 10 were considered. Finally, we created a gene-disease target network using CYTOSCAPE version 3.10.0 . The schematic representation of networking of the total of five genes named ADIPOQ, CRP, IL18, IL1RN, and SERPINE1 encode the protein Progestin and adipoQ receptor family member 3, C-reactive protein, Interleukin-18, Interleukin-1 receptor antagonist protein, and SERPINE1 mRNA-binding protein 1 respectively are shown in figure 2.
These five genes (highlighted in Figure) had the highest level of interaction with the disease, as shown in the networking. The PubMed database directly correlates ten genes and various diseases, including immune-inflammatory, autoimmune, cancer, and endocrine diseases. Based on a number of PubMed literature, there is a direct correlation between proinflammatory mediators such as CRP and IL-6R, which has been re-validated through networking. As a result, IL-35, an anti-inflammatory immune suppressant, may be useful in counteracting the pro-inflammatory signals that occur during diabetes and its complications.
IL-35 is a protective factor against diabetes, and it plays a significant role in macrophage polarization. Treg and Th1 cells are crucial for this protection [8]. Studies on non-obese diabetic mice have revealed that IL-35 expression reduces conventional T cells, dendritic cells, and Treg cells against beta cells [9]. The administration of IL-35 also reduces the number of Th1 and Th17 cells, as well as IFN-γ or IL-17A-expressing CD8+ T cells [10]. Thereby, IL-35 plays a critical regulatory role in T1D by decreasing the infiltration of mononuclear cells in the islets [11-12]. Clinical research has provided additional insights, indicating that C-peptide-negative patients exhibit markedly lower serum levels of IL-35 [7-10]. This decrease is associated with a simultaneous reduction in the proportion of IL-35+ Treg cells, IL-35+ regulatory B cells, and IL-35-producing CD8+ FOXP3+ cells [12-14]. These findings highlight the potential significance of IL-35 expression in controlling the immune response and its role in the autoimmune processes underlying T1D. IL-35-mediated immunotherapy has shown promising results in countering diabetes complications. Studies suggest that IL-35 can control cytokine proportions, regulate B cells, and provide protection against autoimmune diabetes. However, further research is required to determine its exact mechanism, with proper planning of clinical trials.