Chronic diseases are often associated with altered inflammatory response, leading to increased host vulnerability to new inflammatory challenges. Employing streptozotocin (STZ)-induced diabetes as a model, we further investigate mechanisms leading to enhanced neutrophil (polymorphonuclear leukocytes, PMN) response under hyperglycemia and compare to that under chronic colitis. We show that, different from colitis under which PMN response is significantly potentiated, the existence of a proinflammatory state associated with broad increases in macrophages in various organs plays a dominant role in promoting PMN inflammatory response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment not through inducing a high level of IL-17, which is the case in colitis, but through increasing F4/80+ macrophages in the peritoneal cavity, resulting in elevations of IL-6, IL-1β, TNF-α, and CXCL1 production. Insulin reversal of hyperglycemia, but not the neutralization of IL-17, reduces peritoneal macrophage numbers and ameliorates PMN infiltration during peritonitis. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and are attributable to exacerbated nephropathy and colitis when inflammatory conditions are induced by doxorubicin and dextran sulfate sodium (DSS), respectively. Furthermore, analyses of monocyte production and macrophage proliferation in tissues suggest significant monocytosis of inflammatory F4/80+Gr-1+ monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages.

Previous studies have suggested that CD47, an essential cell-surface protein, plays an important role in polymorphonuclear neutrophil (PMN) transmigration across tissue cells and extracellular matrix. In the current study, the role of CD47 in PMN transmigration and infiltration into tissues was further evaluated by investigating the function of CD47−/− PMN and inflammatory conditions induced in CD47−/− mice. Using in vitro time-course assays, we found that CD47−/− PMN exhibited no impediment, but slightly enhanced response to and transmigration toward, the chemoattractant fMLF. In vivo analysis in CD47−/− mice by inducing acute peritonitis and aggressive colitis observed consistent results, indicating that both PMN and monocytes effectively infiltrated inflammatory sites despite the absence of CD47 on these leukocytes or the surrounding tissue cells. Although PMN transmigration was not delayed in CD47−/− mice, fewer PMN were found in the intestine at the postacute/chronic stage of chronic colitis induced with sustained low-dose dextran sulfate sodium. Further analysis suggested that the paucity of PMN accumulation was attributable to attenuated granulopoiesis secondary to assessed lower levels of IL-17. Administration of exogenous IL-17A markedly increased PMN availability and rapidly rendered severe colitis in CD47−/− mice under dextran sulfate sodium treatment.

Gliomas are the most common type of primary brain tumors. Despite the improvement in current treatments for gliomas, including surgical resection, radiation, and chemotherapy, there has been very little progress in curing this kind of disease. Stat3 is a member of signal transducer and activator of transcription family. It plays an important role in regulating cell survival, invasion, and apoptosis. This study investigated the influence of low-level expression of Stat3 on invasion and apoptosis in U251 cells. Our data showed that Stat3 is constitutively expressed in human gliomas cell line U251. The invasion activity in U251 cells was weakened and the apoptosis in U251 cells was induced after down-regulation of Stat3. In addition, down-regulation of Stat3 can suppress the expression of MMP-2, Bcl-xL and survivin but not 67LR. These results further indicate that Stat3 plays a key role in the invasion and apoptosis of human glioma cell line U251.

In pancreatic β cells, ATP-sensitive potassium (Κ Α τρ) channels are metabolic sensors that couple cell metabolism to electrical activity, and therefore KATP channels regulate insulin secretion. We assume that down-regulating the expression of Kir6.2 subunits of KATP channels may change calcium influx induced by glucose and insulin secretion regulated by KATP channels. In our study, we employ Kir6.2-shRNA plasmid to downregulate Kir6.2 expression in HIT-T15 cells. Then, we research the effect of downregulation of Kir6.2 on KATP current, cytoplasmic free Ca 2+ concentration and insulin secretion. All results illustrate that downregulation of Kir6.2 subunits of KATP channels in HIT-T15 cells affects KATP current and insulin secretion, and fails to promote calcium influx. The results demonstrate the function of Kir6.2 subunits in electrophysiology characteristic, insulin secretion and calcium influx, and RNA interference provides a feasible alternative to study the function of Kir6.2 subunits in KATP channels in different kinds of diabetes.