ABSTRACT
BACKGROUND: Nickel was recently identified as a potent activator of dendritic cells through ligating with human Toll-like receptor (TLR)-4. OBJECTIVES: Here, we studied an extended panel of transition metals neighbouring nickel in the periodic table of elements, for their capacity to activate human monocyte-derived dendritic cells (MoDCs). METHODS: The panel included chromium, cobalt, and palladium, all of which are known to be frequent clinical sensitizers. MoDC activation was monitored by assessment of release of the pro-inflammatory mediator interleukin (IL)-8, a major downstream result of TLR ligation. Results The data obtained in the present study show that cobalt and palladium also have potent MoDC-activating capacities, whereas copper and zinc, but not iron and chromium, have low but distinct MoDC-activating potential. Involvement of endotoxin contamination in MoDC activation was excluded by Limulus assays and consistent stimulation in the presence of polymyxin B. The critical role of TLR4 in nickel-induced, cobalt-induced and palladium-induced activation was confirmed by essentially similar stimulatory patterns obtained in an HEK293 TLR4/MD2 transfectant cell line. CONCLUSIONS: Given the adjuvant role of costimulatory danger signals, the development of contact allergies to the stimulatory metals may be facilitated by signals from direct TLR4 ligation, whereas other metal sensitizers, such as chromium, may rather depend on microbial or tissue-derived cofactors to induce clinical sensitization.
Subject(s)
Dendritic Cells/immunology , Toll-Like Receptor 4/immunology , Transition Elements/immunology , Biomarkers/metabolism , Cells, Cultured , Chromium/immunology , Chromium/metabolism , Cobalt/immunology , Cobalt/metabolism , Dendritic Cells/metabolism , Dermatitis, Allergic Contact/etiology , Dermatitis, Allergic Contact/immunology , Dermatitis, Allergic Contact/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Interleukin-8/immunology , Interleukin-8/metabolism , Nickel/immunology , Nickel/metabolism , Palladium/immunology , Palladium/metabolism , Toll-Like Receptor 4/metabolism , Transition Elements/metabolismABSTRACT
Evidence is increasing that a defect in apoptosis is involved in the pathogenesis of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). CD seems to be the cause of an intrinsic defect in the apoptotic pathway of (autoreactive) T cells, resulting in excessive T cell responses. In UC, an increased rate of apoptosis of epithelial cells is observed. In this review we will describe apoptotic mechanisms and their association to IBD. In addition, we will review how specific therapeutic approaches interact at different levels with the apoptotic pathway.