Oxidants and Antioxidants Synergistically Activate Immuno-Responses During Tumorgenesis

Abstract

The human immune system possesses powerful surveillance functions to find and eliminate tumor cells. Several steps are involved, such as uptake and presentation of tumor antigens by dendritic cells (DCs) in order to activate T cells, trafficking and infiltration of the tumor with T cells and, finally, recognition and killing of tumor cells. Tumor cells release a number of soluble mediators that may disrupt these steps, thereby creating tolerance or immune escape. We previously published data on a rat animal model showing 1, 2-dimethylhydrazine (DMH) to inhibit DCs activation and enhance T regulatory cells (Treg) expression, ultimately inducing colon carcinogenesis. By feeding rats with mustard seeds (MS), the animals’ immune system shifted from a Th2 to a Th1 pattern, Tregs were inhibited and DCs activation enhanced. In the present study, we tried to isolate the functional fractions of MS and, to our surprise, we found that the oxidant and antioxidant fractions of MS showed synergistic effect on the activation of DCs and CD8+ effector T cells. Neither of the fractions alone, however, had any inhibitory effect on DMH-induced colon carcinogenesis. Differently from the antioxidant fraction, the oxidant fraction activated DCs (CD11c+CD80+, CD11c+CD86+), but not the CD8+ effector T cells. By adding Vitamin E, an acknowledged antioxidant, the oxidant fraction then became able to activate both spleenic DCs and effector T cells (CD8+CD28+). Taken together, these data suggest that the MS oxidant fraction might play an important role in activation of DCs, while also showing that oxidative signals may induce depletion of effector T cells. Addition of the antioxidant MS fraction, or Vitamin E, might restore the survival of effector T cells and eventually help eradicate tumor cells. Thus, MS oxidants, which normally are regarded as having negative effects, may actually function synergistically with antioxidants to prevent chemical-induced carcinogenesis. Keywords: Oxidants; Antioxidants; Immuno-responses; Mustard seeds; Colorectal cancer; Chemoprevention; T cells; Dendritic cells Abbreviations: AITC: Allyl Isothiocyanate; APCs: Antigen-Presenting Cells; CTLs: Cytotoxic T Lymphocytes; DCs: Dendritic Cells; DMH: 1, 2-Dimethylhydrazine; EGCG: Epigallocatechin Gallate; LPO: Lipid Peroxides ; MDA: Malondialdehyde; MHC: Major Histocompatibility Complex; MS: Mustard Seeds; MSE1: Ether Extract of Mustard Seeds; MSE2: Ethanolic Extract of Mustard Seeds; PBS: Phosphate-Buffered Saline; RBC: Red Blood Cell; ROS: Reactive Oxygen Species; TCRs: T Cell Receptors; Treg : T Regulatory Cells; VitE : Vitamin E