Parathyroid hormone induces hepatic production of bioactive interleukin-6 and its soluble receptor

Interleukin-6 (IL-6) is an important mediator of parathyroid hormone (PTH)- induced bone resorption. Serum levels of IL-6 and its soluble receptor (IL- 6sR) are regulated in part by PTH. The PTH/PTH-related protein type 1 recep tor is highly expressed in the liver, and in the current study we investiga ted whether the liver produces IL-6 or IL-6sR in response to PTH. Perfusion of the isolated rat liver with PTH-(1-84) stimulated rapid, dose-dependent production of bioactive IL-6 and the IL-6sR. These effects were observed a t near physiological concentrations of the hormone such that 1 pM PTH induc ed hepatic IL-6 production at a rate of similar to0.6 ng/min. In vitro, hep atocytes, hepatic endothelial cells, and Kupffer cells, but not hepatic ste llate cells, were each found to produce both IL-6 and IL-6sR in response to higher (10 nM) concentrations of PTH. Our data suggest that hepatic-derive d IL-6 and IL-6sR contribute to the increase in circulating levels of these cytokines induced by PTH in vivo and raise the possibility that PTH- induc ed, liver-derived IL-6 may exert endocrine effects on tissues such as bone.