a novel dc therapy with manipulation of mkk6 gene on nickel allergy in mice一种新型直流治疗操纵mkk6基因在小鼠镍过敏.pdfVIP

A Novel DC Therapy with Manipulation of MKK6 Gene on Nickel Allergy in Mice 1,2 1 1,2 1 1 Megumi Watanabe , Naozumi Ishimaru *, Meinar Nur Ashrin , Rieko Arakaki , Akiko Yamada , Tetsuo Ichikawa2, Yoshio Hayashi1 1 Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan, 2 Department of Oral Maxillofacial Prosthodontics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan Abstract Background: Although the activation of dermal dendritic cells (DCs) or Langerhans cells (LCs) via p38 mitogen-activated protein kinase (MAPK) plays a crucial role in the pathogenesis of metal allergy, the in vivo molecular mechanisms have not been identified and a possible therapeutic strategy using the control of dermal DCs or LCs has not been established. In this study, we focused on dermal DCs to define the in vivo mechanisms of metal allergy pathogenesis in a mouse nickel (Ni) allergy model. The effects of DC therapy on Ni allergic responses were also investigated. Methods and Finding: The activation of dermal DCs via p38 MAPK triggered a T cell-mediated allergic immune response in this model. In the MAPK signaling cascade in DCs, Ni potently phosphorylated MAP kinase kinase 6 (MKK6) following increased DC activation. Ni-stimulated DCs could prime T cell activation to induce Ni allergy. Interestingly, when MKK6 gene- transfected DCs were transferred into the model mice, a more pronounced allergic reaction was observed. In addition, injection of short interfering (si) RNA targeting the MKK6 gene protected against a hypersensit