Using a model of 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity (CHS) we found that, as compared with wild-type mice, IL-15 receptor a chain (IL-15Ra)-deficient mice showed significantly less ear swelling. This decreased response was associated with diminished expression of CCL5/RANTES and CXCL10/IP-10, chemokines critical for effector cell recruitment, in the inflamed tissue. We determined that both the number of CD8 + T cells infiltrating the affected skin and the production of CCL5/RANTES by antigen-stimulated CD8 + T cells were decreased in IL-15Ra -/-mice. The lower levels of CXCL10/IP-10 suggested that the IL-15Ra -/-mice had reduced production of IFN-c, the primary inducer of CXCL10/IP-10, which was in fact the case. However, by contrast with CCL5/RANTES, the diminished levels of IFN-c were likely due to the decreased number of skin-infiltrating CD8 + T cells, since IFN-c production by antigen-stimulated CD8 + T cells was comparable between wild-type and IL-15Ra -/-mice. Our data suggest a positive, pro-inflammatory feedback loop involving CCL5/ RANTES, IFN-c and CXCL10/IP-10 that underlies the CHS reaction and that is disrupted, likely primarily by a defect in CCL5/RANTES production, in mice lacking IL-15Ra, resulting in impaired leukocyte recruitment and inflammation. Moreover, it is particularly noteworthy that the defect in CCL5/RANTES expression in CD8 + T cells is intrinsic to the absence of IL-15Ra, indicating that IL-15Ra is critical for CCL5/ RANTES expression in CD8 + T cells.

Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders, the therapeutic strategy of which it is limited due to its complex pathogenesis. Oxidative stress-induced damage in gastric mucosal epithelial cells is related to the pathogenesis and development of FD. Quercetin (Que) is one of the active ingredients of Zhishi that showed antioxidant, antiapoptotic, and anti-inflammatory effects. The aim of this study is to investigate the effect of Que on oxidative stress-induced gastric mucosal epithelial cells damage and its underlying molecular mechanism. The gastric mucosal epithelial cell line GES-1 was treated with 200 μM of H2O2 to construct an oxidative stress-induced damage model. The H2O2 cells were then administrated with different concentrations of Que. The results indicated that high concentration of Que (100 μM) showed cytotoxicity in H2O2-induced GES-1 cells. However, appropriate concentration of Que (25 and 50 μM) alleviated the oxidative stress damage induced by H2O2, as demonstrated by the increase of proliferation, decrease of ROS generation, apoptosis, inflammation, and alleviation of mitochondrial function and cell barrier. In addition, Que increased the activation of phosphorylation of PI3K and AKT decreased by H2O2. To investigate whether Que alleviated the oxidative stress damage in GES-1 cells by the PI3K/AKT signaling pathway, the GES-1 cells were treated with Que (25 μM) combined with and without LY294002, the PI3K inhibitor. The results showed that LY294002 suppressed the alleviation effect on Que in H2O2-induced GES-1 cells. In conclusion, the current study demonstrates that Que alleviates oxidative stress damage in GES-1 cells by improving mitochondrial function and mucosal barrier and suppressing inflammation through regulating the PI3K/AKT signaling pathway, indicating the potential therapeutic effects of Que on FD.

Patients with type 1 diabetes mellitus are associated with impairment in vitamin A metabolism. This study evaluated whether treatment with retinoic acid, the biologically active metabolite of vitamin A, can ameliorate diabetes. All-trans retinoic acid (atRA) was used to treat streptozotocin (STZ)-induced diabetic mice which revealed atRA administration ameliorated blood glucose levels of diabetic mice. This hyperglycemic amelioration was accompanied by an increase in the amount of β cells co-expressed Pdx1 and insulin and by restoration of the vascular laminin expression. The atRA-induced production of vascular endothelial growth factor-A from the pancreatic islets was possibly the key factor that mediated the restoration of islet vascularity and recovery of β-cell mass. Furthermore, the combination of islet transplantation and atRA administration significantly rescued hyperglycemia in diabetic mice. These findings suggest that vitamin A derivatives can potentially be used as a supplementary treatment to improve diabetes management and glycemic control.

The ATP-binding cassette transporter ABCG2 is expressed in the interfollicular epidermis and mediates the side-population phenotype in skin cells. However, the role of ABCG2 in skin is unclear. Increased expression levels of ABCG2 were found at the basal layer of transitional epidermis adjacent to cutaneous wounds in human patients, indicating that ABCG2 may be involved in regulating the wound healing process. To investigate the role of ABCG2 in cutaneous wound healing, full-thickness skin wounds were created in ABCG2 knockout (ABCG2-KO) and wild-type mice. The healing process was analysed and revealed that ABCG2 deficiency in skin results in delays in wound closure and impairments in re-epithelialization, as evidenced by reductions in both suprabasal differentiation and in p63-expressing keratinocytes migrating from transitional epidermis to epithelial tongues. The reduction in p63-expressing cells may be due to elevated levels of reactive oxygen species in ABCG2-KO epidermis, which can cause DNA damage and lead to proliferation arrest. To determine whether ABCG2 deficiency affects the potency of epidermal stem/progenitor cells (EPCs), transplantation studies were carried out, which demonstrated that ABCG2-KO EPCs display higher levels of γH2AX and lose the capacity to differentiate into suprabasal keratinocytes. A competitive repopulation assay confirmed that ABCG2 expression is critical for the proper expansion and differentiation of EPCs in cutaneous wounds. As EPCs are known to contribute to the healing of larger wounds, the current findings imply a functional role for ABCG2 in the expansion and differentiation of p63-expressing EPCs. Thus, ABCG2 deficiency in skin impairs re-epithelialization in cutaneous wound healing.

Patients with chronic pancreatitis are at increased risk of developing pancreatic cancer. However, the key inflammatory action mediating pancreatic tumorigenesis has not been clearly determined. Here, we initially identified evaluated levels of activated glucocorticoid receptors (GR) were observed in patients of chronic pancreatitis and pancreatic ductal adenocarcinomas (PDAC). Utilizing mice that conditionally expressed KrasG12D in acinar cell compartment with or without loss of GR, we demonstrated that activation of GR was required for generation of metaplastic ductal lesion and development of pancreatic intraepithelial neoplasia (PanIN) in mice with experimental pancreatitis. Administration of dexamethason, a potent synthetic glucocoticoid, was sufficient to induce development of advanced PanINs and metastatic PDACs in KrasG12D mice that harbour single-allele deletion of p53. We further revealed that nongenomic activation of GR was a key action that led to evaluating c-Src signaling and triggering a pathological threshold of Ras activity necessary for neoplastic transformation. In contrast, treatment of dasatinib, a Src kinase inhibitor, could suppressed development of PanIN and PDAC induced by dexamethasone. Importantly, cre-lox based lineage-tracing mice was applied and identified that GR activation directly transformed GFP-tagged KrasG12D-expressing acinar cells to tumorigenic cells that posse features of cancer initiating cells. The findings explained why chronic inflammation increase pancreatic cancer risk and raised concerns on the use of glucocorticoids on patients of chronic pancreatitis Citation Format: Chia-Ning Shen, Chien-Chang Su, Chi-Chih Hsieh, Wen-Ying Liao, Wan-Yu Mao, Chia-Rui Shen, Michael Hsiao. Activated glucocorticoid signaling in pancreatitis contributes to acinar-to-ductal metaplasia and KrasG12D-driven tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B16. doi: 10.1158/1557-3125.RASONC14-B16