IL‐23 leads to diabetes induction after subdiabetogenic treatment with multiple low doses of streptozotocin

Abstract

IL-23, a proximal regulator of IL-17, may be a major driving force in the induction of autoimmune inflammation. We have used a model of subdiabetogenic treatment with multiple low doses of streptozotocin (MLD-STZ; 4 Â 40 mg/kg body weight) in male C57BL/6 mice to study the effect of IL-23 on immune-mediated b cell damage and the development of diabetes, as evaluated by blood glucose, quantitative histology, immunohistochemistry and expression of relevant cytokines in the islets. Ten daily injections of 400 ng IL-23, starting on the first day of MLD-STZ administration led to significant and sustained hyperglycemia along with weight loss compared with controls (no IL-23), and a significant increase in the number of infiltrating cells, a lower insulin content, enhanced apoptosis, expression of IFN-c and IL-17 (not seen in the controls) and a significant increase in the expression of TNF-a and IL-18 in the pancreatic islets. IL-23 treatment started 5 days prior to MLD-STZ administration had no effect on diabetogenesis or cytokines expression in the pancreatic islets. We provide the first evidence in an animal model that IL-23 is involved in the development of type-1 diabetes, by inducing IL-17 and possibly IFN-c production in the target tissue.

IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

“…Although IL-17 plays a major role in the inflammatory response in autoimmune diseases such as EAE, its role in autoimmune diabetes remains poorly understood. Diabetes induction can be accelerated by IL-23 treatment that leads to IL-17 induction (20), and IL-17 has been shown to increase the level of inducible nitric oxide (NO) synthase in pancreatic ␤ cells, leading to the production of NO and subsequent ␤ cell damage (27). Nevertheless, the effects of blocking IL-17 are variable depending on circumstances.…”

“…Although the role of IL-17-producing cells in the development of diabetes has not been definitively addressed, it has been suggested that these cells may contribute to the pathogenicity of autoreactive T cells in the disease (19,20). The recently elucidated role for IL-21 in the development of Th17 cells (6-8) therefore suggested that Th17 cells might play a role in the IL-21-mediated development of diabetes, and increased IL-17 levels have been identified in the later phase of progression from insulitis to active diabetes (21).…”

T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORγt inhibition in autoimmune diabetes

“…IL-23 is considered to be a major driving force in the induction of autoimmune inflammation. Recent study [39] has shown that in an animal model IL-23 is involved in the development of T1D, by inducing IL-17 and possibly IFN-γ production in the target tissues.…”

“…It has been established that five daily doses of 40 mg/kg/day are required for delayed onset, sustained and progressive hyperglycemia and insulitis in male C57BL/6 mice and the 4-day injection of STZ did not induce significant hyperlycemia and only led to mild single cell insulitis [39].…”

CD4 T cells producing pro-inflammatory interleukin-17 mediate high pathology in schistosomiasis

“…The origin of IL-23 and other possible activating signals is ascribed to innate immunocytes, although the precise pathogen-derived stimuli are not known. Th IL-17 cells have been shown to participate in an increasing number of host responses stimulated by a variety of self antigens and pathogens (Infante-Duarte et al 2000, Lubberts et al 2004, Happel et al 2005, Khader et al 2005, Langrish et al 2005, Kleinschek et al 2006, Mensah-Brown et al 2006. It now is of great interest and importance to ascertain their presence and activity in human diseases including schistosomiasis.…”