AbstractReceptor activator of NF‐κB (RANK) ligand (RANKL) and osteoprotegerin (OPG) play essential roles in bone metabolism and immune responses. RANKL activates RANK, which is expressed by osteoclasts and dendritic cells (DC), whereas OPG acts as its decoy receptor. The role of RANKL and OPG in thyroid physiology is unclear. Northern analysis revealed pronounced OPG mRNA levels in normal human thyroid. By contrast, RANKL mRNA levels were most abundant in lymph node and appendix, and low in the thyroid. In the human thyroid follicular cell line XTC and in primary human thyroid follicular cells, OPG mRNA levels and protein secretion were upregulated by interleukin (IL)‐1β ?(33‐fold), tumor necrosis factor (TNF)‐α (eightfold), and thyrotropin (TSH) (threefold). RANKL mRNA was stimulated in XTC by IL‐1β? and TNF‐α, but inhibited by TSH. Conditioned medium harvested from IL‐1β‐treated XTC (containing high concentrations of OPG) inhibited RANKL‐induced CD40 upregulation and cluster formation of DC. OPG mRNA levels were three times more abundant in surgical thyroid specimens of Graves' disease as compared to other thyroid diseases. Our data suggest that RANKL and OPG are produced in the thyroid gland by thyroid follicular cells, are regulated by cytokines and TSH, and are capable of modulating dendritic cell functions. Thus, these cytokines may represent important local immunoregulatory factors involved in the pathogenesis of autoimmune thyroid diseases. J. Cell. Biochem. 86: 642–650, 2002. © 2002 Wiley‐Liss, Inc.