Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets

Abstract

Cytokines play crucial roles in orchestrating complex multicellular interactions between pancreatic β cells and immune cells in the development of type 1 diabetes (T1D) and are thus potential immunotherapeutic targets for this disorder. Cytokines that can induce regulatory functions—for example, IL‐10, TGF‐β and IL‐33—are thought to restore immune tolerance and prevent β‐cell damage. By contrast, cytokines such as IL‐6, IL‐17, IL‐21 and TNF, which promote the differentiation and function of diabetogenic immune cells, are thought to lead to T1D onset and progression. However, targeting these dysregulated cytokine networks does not always result in consistent effects because anti‐inflammatory or proinflammatory functions of cytokines, responsible for β‐cell destruction, are context dependent. In this review, we summarise the current knowledge on the involvement of well‐known cytokines in both the initiation and destruction phases of T1D and discuss advances in recently discovered roles of cytokines. Additionally, we emphasise the complexity and implications of cytokine modulation therapy and discuss the ways in which this strategy has been translated into clinical trials.

COVID-19-Induced Diabetic Ketoacidosis and Acute Respiratory Distress Syndrome in an Obese 24-Year-Old Type I Diabetic

“…Numerous studies have demonstrated that the development of ketoacidosis and hyper-glycemia precipitate an inflammatory state due to elevations in proinflammatory cytokines as well as oxidative stress [ 8 – 10 ]. Hyperglycemia induces macrophages to produce interleukin (IL)-1, IL-6, C-reactive peptide, and tumor necrosis factor-alpha, which reduce the body’s responsiveness to insulin [ 8 – 11 ].…”

Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice

“…Pancreatic β cell damage due to apoptosis plays an important role in both types of DM. In T1DM, β cell destruction occurs following an autoimmune reaction, which triggers activation of inflammatory cells and secretion of cytokines [ 8 ]. This will eventually activate the apoptotic pathways in the pancreatic β cells [ 9 ].…”

“…One of the major signaling pathways that is heavily involved in the regulation of cell apoptosis, survival, and regeneration is the Hippo pathway [ 11 ]. The core components of the Hippo pathway in mammals include kinases—mammalian sterile 20-like kinase 1/2 (MST1/2) and large tumor suppressor 1/2 (LATS1/2), adaptor molecules (salvador (SAV1) and MOB kinase activator 1 (MOB1)), the transcriptional co-activators Yes-associated protein (YAP), and WW domain containing transcription regulator 1 (WWTR1/TAZ) [ 8 , 11 ]. Activation of the Hippo pathway by phosphorylation of the kinases results in YAP inactivation and hence reduces the expression of its target genes, which include anti-apoptotic and pro-survival genes.…”

“…Activation of the Hippo pathway by phosphorylation of the kinases results in YAP inactivation and hence reduces the expression of its target genes, which include anti-apoptotic and pro-survival genes. On the other hand, inhibition of the Hippo pathway result in YAP activation and eventually in induction of target genes expression [ 8 , 11 ].…”

Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts

“…Among the genes that we identified to be differentially expressed in NOD and B6 ES cells, many were known to be involved in innate and adaptive immune responses. While some cytokines promote a tolerogenic environment, such as TGF-b or IL-10, others are known to support a diabetogenic environment, such as TNF and IL-6 [47]. Thus, we investigated whether NOD and B6 ES cells are already capable of responding to certain triggers of the innate immune system, and consequently might secret cytokines.…”