ABSTRACT
Fucoidans have been extensively studied for their various biological activities but the exact role of fucoidans on the inflammatory processes associated with arthritic disease has not been studied. The effect of the treatment of high, medium and low molecular weight fucoidans (HMWF, MMWF and LMWF, respectively) on the progression of collagen-induced arthritis (CIA) was tested. A daily oral administration of HMWF enhanced the severity of arthritis, inflammatory responses in the joint cartilage and the levels of collagen-specific antibodies, while LMWF reduced the severity of arthritis and the levels of Th1-dependent collagen-specific IgG(2a). Further in vitro analyses, using macrophage cell lines, revealed that the HMWF induced the expression of various inflammatory mediators, and enhanced the cellular migration of macrophages. These stimulatory effects of fucoidan decreased in fucoidans with lower molecular weights and LMWF did not exhibit any pro-inflammatory effects. Interestingly, the oral administration of HMWF enhanced the production of IFN-gamma, one of the Th1 cytokines, in collagen-stimulated spleen cells that had been isolated from CIA mice, while LMWF had the opposite effect. These results indicate that HMWF enhances arthritis through enhancing the inflammatory activation of macrophages while LMWF reduces arthritis through the suppression of Th1-mediated Immune reactions.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Cartilage/drug effects , Joints/drug effects , Plant Extracts/therapeutic use , Polysaccharides/therapeutic use , Undaria/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/immunology , Arthritis, Experimental/metabolism , Cartilage/metabolism , Cartilage/pathology , Cell Movement/drug effects , Collagen Type II , Immunoglobulin G/blood , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Inflammation Mediators/metabolism , Interferon-gamma/biosynthesis , Joints/metabolism , Joints/pathology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred DBA , Molecular Weight , Phytotherapy , Plant Extracts/pharmacology , Polysaccharides/chemistry , Polysaccharides/pharmacology , Severity of Illness Index , Spleen/cytology , Spleen/metabolism , Th1 Cells/metabolismABSTRACT
The molecular action mechanism of MRP, one of the protein kinase C (PKC) substrates, has been under intense investigation, but reports on its role in macrophage function remain controversial. The treatment of macrophage cell lines with bacterial lipopolysaccharide (LPS) induced a high level of MRP expression suggesting that MRP plays a role in the function of activated macrophages. In order to investigate the role of MRP in activated RAW264.7 cells, we stably transfected MRP-specific shRNA expression constructs and tested for alterations in macrophage-related functions. The down-regulation of MRP expression resulted in a marked reduction in chemotaxis toward MCP-1 or extracellular matrix proteins. Furthermore, pharmacological inhibitors of PKC significantly inhibited the chemotaxis in RAW264.7 cells. These data reveals the pivotal role of MRP in the transmigration of activated RAW264.7 cells.
