fr-167653 and Lupus-Nephritis

Dendritic cells (DC) contribute to autoimmune disease progression and pathogenesis. Mature DC have been reported to secrete high mobility group box protein (HMGB-1), a novel inflammatory cytokine, via p38 mitogen-activated protein kinase (MAPK) activation. We investigated whether DC are involved in progression of autoimmune diseases followed by secretion of HMGB-1 via p38 MAPK activation in a lupus-prone mouse model.. FR167653, a specific inhibitor of p38 MAPK, was given orally from 3 months of age in MRL-Fas(lpr) mice. Cultured DC, treated with or without FR167653, were stimulated with tumor necrosis factor-alpha.. Inhibition of p38 MAPK led to a reduction in the number of CD11c-positive cells, including those with the mature phenotype, in the diseased kidney and spleen, which resulted in improvement of kidney pathology in MRL-Fas(lpr) mice. The number of CD11c-positive cells in circulation was also reduced. HMGB-1 protein and transcripts detected in the diseased kidney, and the number of cells dual-positive for HMGB-1 and CD11c, were reduced by inhibition of p38 MAPK. Maturation of cultured DC and increased cytokines, including HMGB-1, in the supernatant were inhibited by FR167653 treatment. These results suggest that DC are involved in the progression of autoimmune kidney diseases in MRL-Fas(lpr) mice followed by HMGB-1 secretion via p38 MAPK activation.. Our results indicated that DC secrete HMGB-1 via p38 MAPK activation to participate in autoimmunity in MRL-Fas(lpr) mice.

Topics: Animals; Autoimmune Diseases; CD11c Antigen; Cell Count; Cell Proliferation; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Disease Progression; Enzyme Activation; Enzyme Inhibitors; HMGB1 Protein; Kidney; Lupus Nephritis; Mice; Mice, Mutant Strains; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyrazoles; Pyridines