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

J Cell Physiol. 1992 Oct;153(1):206-13. doi: 10.1002/jcp.1041530125.


The effects of the monokines tumor necrosis factor alpha (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 adenylate cyclase, with maximal inhibition of PTH response (40% for TNF, 24% for IL 1) occurring at 10(-8) M of either monokine. 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 nonreceptor-mediated enzyme activation by cholera toxin and forskolin; both monokines increased prostaglandin E2 stimulation of adenylate cyclase. Binding of the radioiodinated agonist mono-[125I]-[Nle8,18, 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. Pertussis toxin increased PTH-sensitive adenylate cyclase activity but did not attenuate monokine-induced inhibition of PTH response. In time course studies, brief (1 hr) 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 indicate that TNF and IL 1 impair responsiveness to PTH (and PTHrP) by a time- and protein synthesis-dependent down-regulation of PTH receptors linked to adenylate cyclase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclase Inhibitors*
  • Adenylyl Cyclases / metabolism
  • Animals
  • Down-Regulation / drug effects
  • Interleukin-1 / pharmacology*
  • Kinetics
  • Osteoblasts / drug effects*
  • Osteoblasts / enzymology
  • Osteoblasts / metabolism
  • Parathyroid Hormone / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Cell Surface / metabolism*
  • Receptors, Parathyroid Hormone
  • Recombinant Proteins / pharmacology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Adenylyl Cyclase Inhibitors
  • Interleukin-1
  • Parathyroid Hormone
  • Receptors, Cell Surface
  • Receptors, Parathyroid Hormone
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Adenylyl Cyclases