PD-US detects synovitis causing joint destruction even when the patient is in clinical remission. Thus, remission visible on US is essential to reach "true remission" of RA.

IntroductionToll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 (an inducible heme-degrading enzyme that is induced by various stresses) suppresses inflammatory responses. We investigated the interaction between TLR and HO-1 in an inflammatory disorder, namely Behçet's disease.MethodsThirty-three patients with Behçet's disease and 30 healthy control individuals were included in the study. Expression levels of HO-1, TLR2 and TLR4 mRNA were semiquantitatively analyzed using a real-time PCR technique, and HO-1 protein level was determined by immunoblotting in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes. In some experiments, cells were stimulated with lipopolysaccharide or heat shock protein-60; these proteins are known to be ligands for TLR2 and 4.ResultsLevels of expression of HO-1 mRNA were significantly reduced in PBMCs from patients with active Behçet's disease, whereas those of TLR4, but not TLR2, were increased in PBMCs, regardless of disease activity. Moreover, HO-1 expression in PBMCs from patients with Behçet's disease was repressed in the presence of either lipopolysaccharide or heat shock protein-60.ConclusionThe results suggest that upregulated TLR4 is associated with HO-1 reduction in PBMCs from patients with Behçet's disease, leading to augmented inflammatory responses.

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PD-US detects synovitis causing joint destruction even when the patient is in clinical remission. Thus, remission visible on US is essential to reach "true remission" of RA.

NF-κB signaling pathway plays a pivotal role in inflammatory response, and its excessive activation causes systemic inflammatory disorder, such as systemic lupus erythematosus (SLE). TRIM21, one of the tripartite motif (TRIM) family members, is an E3 ubiquitin ligase that functions in both innate and acquired immunity. It is also an autoantigen known as Ro52/SS-A, which is observed in patients with SLE. Recent studies, including Trim21 gene disruption studies, suggest that TRIM21 is a negative regulator for NF-κB-dependent proinflammatory cytokine production. However, the molecular mechanism still remains to be clarified. Here we report that TRIM21 interacted with tumor necrosis factor-associated factor 6 (TRAF6), an essential adaptor protein for Toll-like receptor/interleukin 1 receptor (TLR/IL-1R)-mediated activation of NF-κB signaling pathway. The TRIM21-TRAF6 interaction was indirect and mediated by a scaffold protein, p62/sequestosome 1. TRIM21-overexpressed fibroblast cell line showed decreased expression of TRAF6 as compared to the control cells. TRIM21 promoted not only K63-linked ubiquitylation but also K48-linked ubiquitylation of TRAF6 in the presence of p62. Furthermore proteasome inhibitor MG132 increased the ubiquitylated TRAF6 proteins. These data suggest that the function of TRIM21 as a negative regulator for NF-κB signaling is attributed to the proteasome-mediated degradation of TRAF6.