Rheumatoid arthritis is a chronic autoimmune inflammatory disease that affects 1% of the population. Disease selleck Volasertib progression is characterized by a destructive inflammation of the joints, which can lead to progressive disability and a reduced life expectancy. The synovial membrane in RA is infiltrated by activated immune cells, most abundantly macrophages and T cells, resulting in the chronic production of pro inflammatory cytokines and matrix metalloproteinases, leading to inflammation and cartilage and bone degradation. The treatment of RA has been revolutionized by the development of biolo gical therapies specifically targeting immune mediators. These include tumor necrosis factor, interleu kin 1, the IL 6 receptor, B cells, and activated T cells.

However, these biologics are not orally available and are expensive to manufacture, their cost severely limits use. Side effects are also common, for example, systemic inhibition of TNF confers an increased risk Inhibitors,Modulators,Libraries of infection in patients. Thus, there is a require ment for cheaper and more Inhibitors,Modulators,Libraries targeted therapies to treat RA. To improve the therapies available to patients, it is essential to gain a better understanding of the mechan isms that sustain inflammation in RA. Despite the effec tiveness of biological therapies in many patients, disease activity usually resumes once treatment has stopped. This indicates that the upstream mechanisms that generate inflammation are still functional and most likely unaf fected by these treatments. Many studies from both mur ine and human models have suggested a role for a family of innate immune receptors, the Toll like receptors in RA pathogenesis.

TLRs form part of Inhibitors,Modulators,Libraries a network of receptors that alert the host to the presence of infection and tissue Inhibitors,Modulators,Libraries damage. TLRs can be classified into Inhibitors,Modulators,Libraries two distinct groups on the basis of cellular distribution and ligand repertoire. Cell surface expressed TLRs 1, 2, 4, 5, and 6 recognize ligands of mainly bacterial and fungal origin, whereas TLRs 3, 7, 8, and 9 are expressed intracellularly in endosomes and detect nucleic acids from bacteria and viruses. TLR activation induces a strong inflammatory response, which is characterized by the increased expression of TNF among many other mediators. In addition to pathogen associated ligands, TLRs can engage a number of endo genous molecules that Oligomycin A cost can be produced during tissue damage and are often found at the sites of chronic inflammation. The concept of endogenous ligand driven activation of TLRs makes these receptors potential candidates for the induction or maintenance of chronic inflamma tory conditions.