[Show abstract][Hide abstract] ABSTRACT: Hapten-induced contact hypersensitivity (CHS) in the skin is a delayed type cellular immune response that can be mediated by CD8(+) T cells that produce IFN-gamma or IL-17. However, mechanisms for these cytokines in the elicitation of CHS remain to be fully elucidated. In this study, we show that adoptive transfer of CHS with hapten-primed wild-type (WT) CD8(+) T cells is reduced in IFN-gammaR(-/-) or IL-17R(-/-) mice compared with WT controls. The infiltration of granulocytes and macrophages in the hapten challenged skin of IL-17R(-/-) recipients is significantly reduced whereas it is less affected in IFN-gammaR(-/-) recipients although CD8(+) T cell infiltration is inhibited in both recipients. In contrast, the activity of reactive oxidative species is significantly inhibited in IFN-gammaR(-/-) but is less affected in IL-17R(-/-) recipients. Further analysis reveals that the expression of chemokines and cytokines is differentially regulated in the hapten-challenged skin of IFN-gammaR(-/-) or IL-17R(-/-) recipients compared with WT controls. Interestingly, injection of rIL-17 in the skin induces inflammation with a high level of leukocyte infiltration whereas injection of IFN-gamma induces inflammation with a high level of reactive oxidative species. Moreover, neutralization of IL-17 in IFN-gammaR(-/-) or IFN-gamma in IL-17R(-/-) mice further suppresses the adoptive transfer of CHS by hapten-primed WT CD8(+) T cells. The study demonstrates that IFN-gamma and IL-17 mediate the elicitation of CHS by different mechanisms and that both cytokines are required for optimal responses. This outcome improves understanding of pathogenesis and provides new insights into therapeutic strategies for CHS.
The Journal of Immunology 07/2009; 183(2):1463-70. DOI:10.4049/jimmunol.0804108 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Slits are a group of secreted glycoproteins that play a role in the regulation of cell migration. Previous studies suggested that Slit2 might be a tumor-suppressor gene. However, it remained to be determined whether Slit2 suppressed tumor growth and metastasis in animal models. We showed that Slit2 expression was decreased or abolished in human esophageal squamous cell carcinomas (SCCs) compared to normal tissues by in situ hybridization. Stable transfection of human SCC A431 and fibrosarcoma HT1080 cells with Slit2 gene suppressed tumor growth in athymic nude mice. Apoptosis in Slit2-transfected tumors was increased, whereas proliferating cells were decreased, suggesting a mechanism for Slit2-mediated tumor suppression. This was supported by further analysis indicating that antiapoptotic molecules Bcl-2 and Bcl-xl and cell cycle molecules Cdk6 and Cyclin D1 were down-regulated in Slit2-transfected tumors. Furthermore, wound healing and Matrigel invasion assays showed that the transfection with Slit2 inhibited tumor cell migration and invasion. Slit2-transfected tumors showed a high level of keratin 8/18 and a low level of N-cadherin expression compared to empty vector-transfected tumors. More importantly, Slit2 transfection suppressed the metastasis of HT1080 tumor cells in lungs after intravenous inoculation. Collectively, our study has demonstrated that Slit2 inhibits tumor growth and metastasis of fibrosarcoma and SCC and that its effect on cell cycle and apoptosis signal pathways is an important mechanism for Slit2-mediated tumor suppression.
Neoplasia (New York, N.Y.) 01/2009; 10(12):1411-20. DOI:10.1593/neo.08804 · 4.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Apoptosis plays an important role in eliminating UV-damaged keratinocytes, but its role in UV-induced immune suppression is not clear. Langerhans cells (LCs) may function as inducers of immune suppression. We have shown that LCs derived from mice deficient in the proapoptotic Bid (BH3-interacting death domain protein) gene (Bid KO) resist apoptosis and induce amplified immune responses. In this report, we examined responses in Bid KO mice to UVB exposure. Acute UV exposure led Bid KO mice to develop fewer apoptotic cells and retain a greater fraction of LCs in the epidermal layer of skin in comparison to wild-type mice. Bid KO mice were also markedly resistant to local and systemic UV tolerance induction to hapten sensitization and contact hypersensitivity responses. Elicitation responses and inflammation at skin sensitization sites in UV-treated Bid KO mice were equal to or greater than nonsuppressed control responses. In Bid KO mice, LCs accumulated in lymph nodes to greater numbers, demonstrated longer lifespans, and contained fewer DNA-damaged cells. These studies provide evidence that Bid activation is a critical upstream mediator in UV-induced keratinocyte and LC apoptosis and that its absence abrogates UV-induced immune tolerance.
The Journal of Immunology 10/2008; 181(5):3077-88. DOI:10.4049/jimmunol.181.5.3077 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore attitudes toward physical activity among a multiethnic group of midlife women.
A qualitative cross-sectional study using an online forum. RECRUITMENT SETTINGS: Internet communities/groups for midlife women and for ethnic minorities.
A multiethnic group of 15 midlife women.
Ten online forum topics on attitudes toward physical activity and seven on ethnic-specific contexts.
Thematic analysis, involving line-by-line coding, categorization, and theme extraction.
Six themes across all ethnic groups emerged from the data analysis process, although there were some ethnic differences in details related to each theme. The themes were (a) gendered experience, (b) physical activity as all body movements, (c) no time for physical activity, (d) environment matters, (e) health concerns made me do it, and (f) need a companion.
Nurses need to consider and further investigate the influence of women's multiple roles, cultural factors, and environmental factors on physical activity in order to promote physical activity of midlife women.
[Show abstract][Hide abstract] ABSTRACT: Allergen-induced contact hypersensitivity (CHS) is a T cell-mediated delayed-type immune response which has been considered to be primarily mediated by CD8+ T cytotoxic type I (Tc1) cells. IFN-gamma, the prototype Tc1 (Th1) cytokine, has been implicated as the primary inflammatory cytokine for CHS. In this study, we demonstrate that neutralization of IL-17 rather than IFN-gamma suppresses the elicitation of CHS. The suppression does not result from inhibition of the proliferation of allergen-activated T cells. Allergen sensitization induces the development of distinct CD8+ T cell subpopulations that produce IFN-gamma or IL-17. Although CD8+ IL-17-producing cells are stimulated by IL-23, they are inhibited by IL-12, a prototypical stimulator of IFN-gamma-producing Tc1 cells. This indicates that CD8+ IL-17-producing cells are distinct from Tc1 cells and are important in effector functions at the elicitation of CHS. These studies provide insights into a novel mechanism for CHS.
The Journal of Immunology 12/2006; 177(10):6852-8. DOI:10.4049/jimmunol.177.10.6852 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A body of evidence indicates that expression of the programmed cell death 1 (PD-1) receptor by activated T cells plays an important role in the down-regulation of immune responses; however, the functions of its known ligands, B7-H1 (PD-L1) and B7-dendritic cell (DC; PD-L2), at the effector phase of immune responses are less clear. In the current study, we investigated the roles of B7-H1 in DC-mediated regulation of hapten-activated T cells and the delayed-type contact hypersensitivity response in primed animals. We found that the expression of B7-H1 and B7-DC was induced on activation of DC by hapten stimulation. Blockade of B7-H1, but not B7-DC, enhanced the activity of hapten-specific T cells. Interaction with a DC line that expresses high cell-surface levels of B7-H1 (B7-H1/DC) suppressed the proliferation of, and cytokine production by, activated T cells. In vivo administration of hapten-carrying B7-H1/DC desensitized the response of sensitized animals to hapten challenge, and this desensitization was hapten-specific. These data indicate that B7-H1 expressed by DC mediates inhibitory signals for activated T cells and suppresses the elicitation of immune responses. The ability of B7-H1/DC to inhibit the function of preactivated T cells in vivo suggests novel strategies for the treatment of immune response-mediated disorders.