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The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure that may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3 alpha (Reg3α) is a pancreatic secretory protein, which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3α production exhibited significantly lower blood glucose levels (9.057 ± 0.59 mmol/l vs 13.48 ± 0.35 mmol/l, P < 0.05) and improved glucose-stimulated insulin secretion (1.80 ± 0.17 ng/ml vs 1.16 ± 0.16 ng/ml, P < 0.05) compared with control group. The decline of apoptotic events (0.57% ± 0.15% vs 1.06% ± 0.07%, P < 0.05) and increased beta-cell proliferation (0.70% ± 0.10% vs 0.36% ± 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3α by morphometric analysis. Further experiments showed that Reg3α production dramatically protected cultured islets and pancreatic beta-cells from cytokine-induced apoptosis and the impairment of glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic beta-cells, which was reversed by Reg3α overexpression in contrast to control group. These results strongly suggest that Reg3α could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.
Interleukin-17 (IL-17 or IL-17A), a pleiotropic cytokine produced by T helper (Th) 17 cells, is involved in the pathogenesis of various autoimmune and inflammatory disorders, including periodontitis. Although the ability of pro-inflammation in periodontitis have been widely investigated, the other biological functions of IL-17, including its role in bone remodeling and the underlying molecular mechanism, have not been well clarified. In the present study, IL-17 could significantly enhance the expression of receptor activator for nuclear factor-κB ligand (RANKL) and inhibit the expression of osteoprotegerin (OPG) in human periodontal ligament cells (hPDLCs), the two critical indicators for osteoclastogenesis, suggesting IL-17 may play a destructive role in the pathogenesis of periodontal bone remodeling. Pharmaceutical signal inhibitors targeted at MAPKs, Akt or NF-κB signals, inhibited IL-17-induced RANKL and OPG regulation. Notably, the enhancement of RANKL was significantly blocked by the inhibitors of JNK and NF-κB signals. The upstream signals were further investigated with the small interfering RNA (siRNA). Both TRAF6 and TBK1 were found to be the critically signal molecules for IL-17-dependent RANKL regulation in hPDLCs. These findings may provide comprehensive understanding of the role of IL-17 in the pathogenesis of periodontitis and might also provide a reasonable way for periodontitis therapy. This article is protected by copyright. All rights reserved.