IL-20 contributes to low grade inflammation and weight gain in the Psammomys obesus.

The metabolic syndrome has been demonstrated in gene deficient animals, e.g. db/db mice, to include a systemic inflammation leading to insulin resistance, obesity and type 2 diabetes (T2D). To determine the importance of inflammation in obesity and diabetes, in a normal non-genetically modified species, an intervention study with neutralizing anti-IL-20 antibodies was conducted in the spontaneous T2D model Psammomys obesus. All IL-20 receptor chains were expressed on protein level in the Psammomys obesus. Neutralization of IL-20 did not modulate blood glucose, HbA1c, insulin levels or lymphocyte numbers after five weeks treatment although a trend to reduced weight gain rate was observed upon anti-IL-20 treatment. Inhibition of IL-20 significantly increased the number of CD11bhigh/low cells and the CD11bGr-1int myeloid derived suppressor cells in the spleen. Importantly, although the number of M1-like monocytes remained unchanged the M1-like marker CD11c expression level was reduced on the cells upon anti-IL-20 treatment. Anti-IL-20 treatment reduced both TLR4 and CCR2b expression on the macrophages upon treatment. Further, a marked shift in the protein signature in the pancreatic tissue after anti-IL-20 treatment was observed including enhanced expression of CXCL12, TIMP-1 and IL-10 while IL-1ß, CXCL4, PEDF and ADAMTS1 were reduced. In conclusion, we describe for the first time the systemic immune response in the diabetic Psammomys obesus. Neutralizing IL-20 modulated the myeloid compartment, the adaptive immunity, and local expression of proteins in the diabetic pancreatic tissue as well as improved on weight gain and hence may place IL-20 as a cytokine to be considered in obesity.

Smad2 Phosphorylation in Diabetic Kidney Tubule Epithelial Cells Is Associated with Modulation of Several Transforming Growth Factor-ß Family Members.

BACKGROUND: The role of transforming growth factor-ß (TGF-ß) has recently gained much attention in diabetic nephropathy and kidney fibrosis. In this study, we extend this to an assessment of transcriptional regulation of the entire TGF-ß superfamily in kidneys from diabetic vs. healthy mice. In order to study the translation between mouse model and patients, we evaluated the signature of phosphorylated Sma- and Mad-related protein 2 (pSmad2), as molecular marker of TGF-ß/activin activity, in the kidneys of streptozotocin (STZ)-treated mice compared to that of type 1 diabetes (T1D) patients. METHODS: Patterns of pSmad2 were determined in kidneys from T1D patients with progressed diabetic nephropathy (DN), defined by hyperglycemia, microalbuminuria, and increased levels of serum creatinine. They were compared to changes seen in the STZ-induced DN mouse model. This was studied by immunohistochemistry (IHC) with an antibody specific for pSmad2. Diabetic mice were also characterized by pSmad1/5/8 (IHC), pSmad2/3 (flow cytometry), and TGF-ß family members including bone morphogenetic protein (BMP)-like proteins (quantitative real-time polymerase chain reaction [qPCR]). RESULTS: Renal tubules in DN patients and in STZ mice showed upregulation of pSmad2 concomitant with significantly enlarged distal tubule lumens (p < 0.0001). Renal-derived CD11b+ cells from STZ mice showed elevated pSmad2/3, while endothelial cells had reduced pSmad2/3 levels. No pSmad1/5/8 was observed in the tubule compartment of STZ-treated mice. On total kidney mRNA level, a signature favoring activation of the TGF-ß/activin pathway and inhibition of the BMP pathway was demonstrated by qPCR. CONCLUSION: Although the pre-clinical DN model lacks the features of fibrosis present in human DN, both species show induction of a local milieu favoring pSmad2 signaling, which may be useful as a disease biomarker in pre-clinical models.