IFN-inducible proteins are known to mediate IFN-directed antitumor effects. The human IFN-inducible protein absent in melanoma 2 (AIM2) gene encodes a 39-kDa protein, which contains a 200-amino-acid repeat as a signature of HIN-200 family (hematopoietic IFN-inducible nuclear proteins). Although AIM2 is known to inhibit fibroblast cell growth in vitro, its antitumor activity has not been shown. Here, we showed that AIM2 expression suppressed the proliferation and tumorigenicity of human breast cancer cells, and that AIM2 gene therapy inhibited mammary tumor growth in an orthotopic tumor model. We further showed that AIM2 significantly increased sub-G 1 phase cell population, indicating that AIM2 could induce tumor cell apoptosis. Moreover, AIM2 expression greatly suppressed nuclear factor-KB transcriptional activity and desensitized tumor necrosis factor-A -mediated nuclear factor-KB activation. Together, these results suggest that AIM2 associates with tumor suppression activity and may serve as a potential therapeutic gene for future development of AIM2-based gene therapy for human breast cancer.

Intestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.

Nitric oxide (NO) derived from the inducible NO synthase (iNOS) is an important and complex mediator of inflammation in the intestine. Wnt-inducible secreted protein (WISP)-1 (CCN4), a member of the connective tissue growth factor family, is involved in tissue repair. We sought to determine the relationship between iNOS and WISP-1 in colitis. By analyzing human colonic biopsy samples, we showed that the expression of mRNA for both iNOS and WISP-1 was significantly higher in ulcerative colitis samples compared with control tissue. The upregulation of WISP-1 was positively correlated with iNOS expression in two models of colitis, induced by intrarectal trinitrobenzenesulfonic acid (TNBS) or occurring spontaneously in IL-10 deficient mice. Loss of iNOS, studied using iNOS(-/-) mice in both TNBS-induced and IL-10(-/-) colitis models, significantly attenuated the colitis-related WISP-1 increase. In human colonic epithelial cell lines, the NO donor, DETA-NONOate, elevated WISP-1 mRNA and protein expression through a beta-catenin and CREB-dependent, but Wnt-1-independent, pathway. In addition, NO-induced WISP-1 directly induced secretion of soluble collagen in colonic fibroblast cells. NO increases WISP-1 expression both in vitro and in vivo, suggesting a new role for iNOS and NO in colitis.

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Neuropeptides such as VIP and PACAP produced or released within the lymphoid microenvironment modulate the immune response through their effect on immune cells bearing specific receptors. In response to antigenic stimulation, CD4+ T cells, and to a lesser degree CD8+ T cells, produce cytokines that play essential roles in the initiation and amplification of various immune responses. VIP/PACAP downregulate the expression of a variety of cytokines such as IL-2, IL-4, and IL-10, by directly affecting the cytokine-producing T cells. Since three types of receptors, PVR1 (the PACAP-preferring receptor), PVR2 (VIP1), and PVR3 (VIP2) bind PACAP/VIP, this study investigated the expression of these receptors in murine T lymphocytes and their role in mediating the inhibition of cytokines. VIP1 and VIP2 agonists, but not PVR1 agonists, inhibit IL-2, IL-4, and IL-10 production, and VIP1 and VIP2, but not PVR1 mRNA, were identified in purified CD4+ and CD8+ splenic T cells. In addition, immunofluorescence studies confirmed the presence of VIP1 and VIP2 on CD4+ and CD8+ T cells. These results indicate that both subsets of peripheral T lymphocytes express VIP1 and VIP2, but not PVR1 receptors, and that the inhibitory effect of VIP/PACAP on IL-2 and IL-10 production is mediated by both VIP1 and VIP2 receptors.

Background Participating in regular physical activity contributes to significant improvements of quality of life (QOL) in adults. Understanding psychosocial factors that influence physical activity and QOL in working adults may have important implications for future interventions aimed at improving their health. The major purpose of this study was to investigate the psychosocial predictors of physical activity and QOL among Shanghai working adults. Methods Participants were 238 working adults ( M age = 51.6 ± 5.6) living in Shanghai communities, China. They completed previously validated questionnaires assessing their perceptions of stress, social support from friends, self-efficacy, physical activity, and QOL. Pearson correlations were computed to assess the associations among physical activity, QOL, and psychosocial variables. Path analysis was used to test the predictive strengths of psychosocial factors on physical activity and QOL among Shanghai working adults. Results The results indicated that stress had directly negative relationships on self-efficacy and QOL. Social support had directly positive relationships on self-efficacy, physical activity, and QOL. Physical activity had directly positive relationship on QOL. Self-efficacy and physical activity mediated the influences of stress and social support on QOL. Conclusions: Stress and social support from friends were two important sources of self-efficacy, all of which facilitated more physical activity participation. Lower stress, higher social support, and more physical activity may directly increase QOL among Shanghai working adults. The mediating roles of self-efficacy and physical activity should be taken into account in managing stress and social support in order to promote QOL among Shanghai working adults.

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