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TNF and IL-1 are both very potent activators of NF-κB and it can be expected that NF-κB activation by these cytokines mediates most of their pro-inflammatory activities in RA (reviewed in [3]).\nNF-κB activation by receptor activator of NF-κB (RANK), a TNF receptor family member, is important for osteoclastogenesis, and defects in proper RANK-NF-κB signalling are likely to be involved in RA pathology and other diseases associated with bone loss [7]. CD40 is another TNF receptor family member that is functionally expressed on a variety of cell types, including smooth muscle fibroblasts from normal and RA patients and RA synovial cells, B cells, macrophages, and dendritic cells, and can be upregulated by proinflammatory cytokines including TNF [10]. Binding of the CD40 ligand (CD154), which is transiently expressed on the surface of activated CD4+ T cells, triggers NF-κB activation resulting in fibroblast proliferation and secretion of proinflammatory cytokines and chemokines, which contributes to joint destruction. However, studies with antagonistic anti-CD40 or anti-CD154 antibodies led to the conclusion that CD40 signals may be important at the initial stages of arthritis induction, but are not required once disease is established and pathogenic antibodies are already present [11,12]. Enhanced expression of the TNF receptor family member B-cell activating factor (BAFF), allowing the survival of autoantibody- producing B lymphocytes, is also characteristic for RA, and antagonists of BAFF have been developed to counter RA [13]. Finally, lymphotoxin β receptor signalling has been implicated in tertiary lymphoid organ formation at sites of chronic inflammation including RA [13].\nToll-like receptors (TLRs) have been implicated in a variety of autoimmune diseases and are potential candidates for inducing NF-κB-dependent inflammation in RA. In addition to microbial ligands, an increasing number of endogenous ligands - a group of proteins derived from host tissues and cells - have been reported as candidate activators of TLRs inducing so-called sterile inflammation (reviewed in [14,15]). TLRs are expressed in RA synovial tissues and various endogenous ligands are present within the inflamed joints of RA patients. Moreover, animal models using TLR knockout mice or strategies to block TLR signalling clearly identify TLR-dependent inflammation as being important in the pathogenesis of the disease.\nHigh mobility group box chromosomal protein 1 (HMGB1), a highly conserved chromatin component that can be actively secreted by macrophages or passively released by necrotic cells, is one of the most putative endogenous TLR4 ligands involved in RA pathology. HMGB1 is increased in RA synovial tissue and HMGB1 neutralising antibodies or the antagonistic BoxA domain of HMGB1 protect against collagen-induced arthritis in mice [16]. Myeloid-related protein 8 and myeloid-related protein 14, damage-associated molecular pattern molecules belonging to the S100 family of calcium-binding proteins, are also abundantly present in RA synovial fluid, and have been suggested to be involved in TLR4-induced chronic inflammation in RA [17,18]. Other endogenous TLR ligands that may be involved in RA pathology are extracellular matrix components such as fibrinogen, fibronectin, biglycan, tenascin C, and hyal-uronic acid fragments (reviewed in [14,15]). Together, these studies suggest that several TLR ligands in the inflamed joint tissue may contribute to NF-κB activation and inflammatory gene expression in 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