Molecular mechanisms controlling NF-kappaB activation in rheumatoid arthritis

Persistent activation of the pivotal transcriptional factor NF-κB within the arthritic joint is a hallmark of rheumatoid arthritis (RA); the molecular mechanisms of that, however, are poorly understood. One objective of this work was to examine two putative mechanisms that may contribute to sustained NF-κB activation in animal models of RA.; First, we found that macrophages lacking CD14, a putative receptor for arthritopathogenic peptidoglycan-polysaccharide complexes (PG-PS) from Gram-positive bacteria, had diminished NF-κB activation and less production of inflammatory cytokines in response to PG-PS in vitro. In addition, the incidence and severity of PG-PS-induced arthritis were significantly reduced in CD14 knockout (KO) mice compared with wild-type mice. Our date indicate that CD14 is an essential receptor in mediating PG-PS-induced NF-κB activation in animal arthritis.; Oxidative stress in the synovium has been implicated in many pathological aspects of RA. We found both incidence and severity of collagen induced arthritis were significantly inhibited in p47phox KO animals, which lack functional NADPH oxidase. This correlated with reduced oxidative stress in the arthritic joints. Our data indicated an essential role for phagocytic NADDH oxidase in development of arthritic pathology by its participation in production of oxidative stress and activation of the innate and adaptive immune responses to self-antigen.; Next, the relationship between NADPH oxidase and NF-κB activation were further examined in p47phox KO fibroblasts. The transcriptional activation of NF-κB was strongly inhibited in p47phox KO cells; however, the classical IκBα-dependent signaling in p47 phox KO cells were comparable to that observed in the wild-type counterparts. Instead, inducible phosphorylation of NF-κB was strongly inhibited in p47phox KO cells. Combined, these results indicated that p47 phox plays an important role in generating intracellular ROS and positive regulation of the transcriptional activation of NF-κB.; The final objective was to test the effect of dietary glycine in experimental arthritis. We found that the severity of PG-PS-induced arthritis was substantially reduced in rats fed with glycine diet. In addition, our data work supports the hypothesis that glycine prevents arthritis by inhibiting superoxide production and blunting NF-κB activation. Therefore, dietary glycine is potentially useful as a new strategy in RA treatment.