Here, for the first time, we showed that macrophages and FLSs can generate large amounts of ORM2, particularly when they are activated by proinflammatory cytokines and LPS, a Toll-like receptor 4 ligand, clearly demonstrating that these cells are major extrahepatic sources of ORM2 production and explaining the elevated ORM2 expression levels in RA joints. This evidence concerns the gene TLR4 and rheumatoid arthritis.