Activation of Discoidin Domain Receptor 1 Facilitates the Maturation of Human Monocyte-Derived Dendritic Cells Through the TNF Receptor Associated Factor 6/TGF-β-Activated Protein Kinase 1 Binding Protein 1β/p38α Mitogen-Activated Protein Kinase Signaling Cascade

摘要: Maturation of dendritic cells (DCs) is critical for their ability to stimulate resting naive T in primary immune responses. Previous studies demonstrated that collagen, such as type I could facilitate DC maturation; however, the basis collagen-mediated maturation remains unclear. Discoidin domain receptor 1 (DDR1) a nonintegrin collagen constitutively expressed variety epithelial cells, including tumor and inducible leukocytes. In this study, we evaluated role DDR1 using human monocyte-derived DCs. Two isoforms, DDR1a DDR1b, were both immature mature Activation on DCs resulted partial activation markedly amplified TNF-alpha- LPS-induced phenotypic functional through p38 mitogen-activated protein kinase (MAPK), suggesting involvement DDR1b process. differentiated DDR1b-overexpressing THP-1 or induced formation TNFR associated factor 6 (TRAF6)/TGF-beta-activated binding 1beta/p38alpha MAPK complex p38alpha autophosphorylation. Transfection with dominant negative TRAF6 completely abrogated DDR1b-mediated phosphorylation, indicating activation. Taken together, our data suggest DDR1b-collagen interaction augments tissue microenvironment unique TRAF6/TGF-beta-activated signaling cascade contributes development adaptive