Tumor necrosis factor and interleukin 1 inhibit parathyroid hormone‐responsive adenylate cyclase in clonal osteoblast‐like cell by down‐regulating parathyroid hormone receptors

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Abstract
The effects of the monokines tumor necrosis factor α (TNF) and interleukin 1 (IL 1) on parathyroid hormone (PTH)‐responsive adenylate cyclase were examined in clonal rat osteosarcoma cells (UMR‐106) with the osteoblast phenotype. Recombinant TNF and IL 1 incubated with UMR‐106 cells for 48 hr each produced concentration‐dependent inhibition of PTH‐sensitive adeylate cyclase, with maximal inhibition of PTH response (40% for TNF. 24% for IL 1) occuring at 10−8 M of either monikine. Both monokines also decreased adenylate cyclase stimulation by the tumor‐derived PTH‐related Protein (PTHrP). In contrast, TNF and IL 1 had little or no inhibitory effect on receptor‐mediated stimulation of adenylate cyclase by isoproterenol and nonreceptors‐mediated enzyme activation by cholera toxin forskolin; both monokines increased prostaglandin E2 stimulation of adenylate cyclase. Binding of the radiodinated agonistt mono‐[125I]‐[Nle3, 18, Tyr34]bPTH‐(1–34)NH2 to UMR‐106 cells in the presence of increasing concentrations of unlabeled [Nle8,18, Tyr34]bPTH‐(1–34)NH2 revealed a decline in PTH receptor density (Bmax) without change in receptor binding affinity (dissociation constant, Kd) after treatment with TNF or IL 1. Pertusis toxin increased PTH‐sensitive adenylate cyclase activity but did not attenuate monokine‐induced inhibiton of PTH response. In time course studies, brief (1hr) exposure of cells to TNF or IL 1 during early culture was sufficient to decrease PTH response but only after exposed cells were subsequently allowed to grow for prolonged periods. Inhibition of PTH response by monokines was blocked by cycloheximide. The results and indicate that TNF and IL 1 impair responsiveness to PTH (and PTHrP) by a time protein synthesis‐dependent down‐regulation of PTH receptors linked to adenylate cyclase.

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