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Abstract: Using mouse gene expression microarray analysis, we earlier obtained dynamic profiles of whole genome expression in the CCl4-induced liver injury mouse model. CXCL14 expression was increased in the liver injury phase and returned to normal after liver regeneration suggesting its involvement in the liver injury or regeneration regulation. The role of CXCL14 in liver injury was investigated. The dynamic of CXCL14 transcription was analyzed in CCl4-induced mouse liver damage by qRT-PCR. Plasmid mediated CXCL14 overexpression and antibody neutralization of endogenous CXCL14 were used to demonstrate its effects and mechanisms on CCl4-induced liver injury and acute liver failure. We showed that CXCL14 expression was immediately upregulated post CCl4 injection with a dose-dependent response. CXCL14 over-expression aggravated CCl4-induced liver injuries, evidenced by enhanced acidophilic change and necrosis of hepatocyte, increased fat deposition in hepatocytes (P <0.01), and inhibited hepatocyte proliferation (P <0.01). On the contrary, anti-CXCL14 antibody treatment reduced the severity of CCL4-induced liver injuries Significant reductions in hepatic necrosis area (P <0.05), the liver fat deposition (P <0.01), and the lipid peroxidation measured by serum MDA (P <0.05) were observed. Importantly, the antibody treatment reduced the mouse mortality caused by CCl4-induced liver failure (P <0.05). The data suggest that CXCL14 and its receptor present potential targets for the treatment of liver diseases. [Copyright &y& Elsevier]

Abstract: Tumor necrosis factor-α induced protein 8 like-2 (TNFAIP8L2, TIPE2), a lately discovered negative regulator of innate immunity and cellular immunity, shares considerable sequence homology with members of the tumor necrosis factor-α induced protein 8 (TNFAIP8) family. It is preferentially expressed in lymphoid-derived and marrow-derived cells. However, it is unclear whether TIPE2 is expressed in the regulatory T cells (Tregs) to contribute to its negative regulatory property in immune response. The present study was designed to examine whether naturally occurring CD4+CD25+ Tregs isolated from murine spleens expressed TIPE2 by the use of Western blot and reverse transcription-polymerase chain reaction (RT-PCR). Based on the expression of cell surface molecules, including cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4+CD25+ Tregs, and cytokines including interleukin (IL)-10 as well as transforming growth factor (TGF)-β were analyzed to investigate the functional role of TIPE2 in controlling suppressive activity of CD4+CD25+ Tregs. Meanwhile, IL-2, the ratio of interferon (IFN)-γ/IL-4 in CD4+CD25+Treg/CD4+CD25− T cell coculture supernatant and nuclear factor of activated T cells (NF-AT) activation in T lymphocytes were determined to examine the effects of TIPE2 on the T-cell proliferation and differentiation induced by CD4+CD25+ Tregs. It was found that TIPE2 was a cytoplasmic protein expressed in CD4+CD25+ Tregs, and cell surface molecules as well as cytokines (IL-10, TGF-β) expressions were significantly down-regulated when TIPE2 gene silenced by siRNA. On the other hand, CD4+CD25+ Tregs treated with TIPE2 knock-down promoted T-cell proliferation as well as differentiation, and markedly upregulated IL-2 expression and intranuclear NF-AT activation. The results suggested that TIPE2 appeared to be a critical immunoregulatory molecule involved in immunosuppressive function of CD4+CD25+ Tregs. [Copyright &y& Elsevier]

Abstract: Chemotherapy induced intestinal mucositis is still an unmet medical problem. 5-fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra has less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy induced intestinal mucositis are warranted. [Copyright &y& Elsevier]

Abstract: Chemotherapy-induced intestinal mucositis is still an unmet medical problem. 5-Fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra had less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy-induced intestinal mucositis are warranted. [ABSTRACT FROM AUTHOR]