title: The mechanisms of up-regulation of dendritic cell activity by oxidative stress.
abstract: Whereas DC have increasingly been recognized for their role in activating the inflammatory cascades during IRIs, the mechanisms by which oxidative stress enhances DC activation remain to be explored. We examined the role of oxidative stress on two important features of DC: T cell activation and trafficking. Bone marrow-derived OS-DC were compared with untreated DC. DC exposed to oxidative stress augmented allogeneic T cell proliferation and showed increased migration in a chemotaxis chamber. These results were confirmed by using hypoxanthine and xanthine oxidase as another inducer of oxidative stress. We used OT-II and OT-I mice to assess the effect of oxidative stress on DC activation of OVA-specific CD4(+) and CD8(+) T cells, respectively. Oxidative stress increased DC capacity to promote OVA-specific CD4(+) T cell activity, demonstrated by an increase in their proliferation and production of IFN-γ, IL-6, and IL-2 proinflammatory cytokines. Whereas oxidative stress increased the DC ability to stimulate IFN-γ production by OVA-specific CD8(+) T cells, cellular proliferation and cytotoxicity were not affected. Compared with untreated DC, oxidative stress significantly reduced the capacity of DC to generate T(regs), which were restored by using anti-IL-6. With regard to DC trafficking, whereas oxidative stress increased DC expression of p-Akt and p-NF-κB, targeting PI3Kγ and NF-κB pathways abrogated the observed increase in DC migration. Our data propose novel insights on the activation of DC by oxidative stress and provide rationales for targeted therapies, which can potentially attenuate IRI.
authors.affiliation: Transplantation Research Center, Departments of Pathology and.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Batal
authors.affiliation: Transplantation Research Center.
authors.forename: Jamil
authors.initials: J
authors.lastname: Azzi
authors.affiliation: Transplantation Research Center.
authors.forename: Marwan
authors.initials: M
authors.lastname: Mounayar
authors.affiliation: Transplantation Research Center.
authors.forename: Rozita
authors.initials: R
authors.lastname: Abdoli
authors.affiliation: Transplantation Research Center.
authors.forename: Robert
authors.initials: R
authors.lastname: Moore
authors.affiliation: Dermatology, and.
authors.forename: Jack Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Departments of Pathology and.
authors.forename: Florencia
authors.initials: F
authors.lastname: Rosetti
authors.affiliation: Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Transplantation Research Center.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.affiliation: Dermatology, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Sackstein
authors.affiliation: Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Transplantation Research Center, rabdi@rics.bwh.harvard.edu.
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: H2O2; T cell activation; migration