Interleukin-6 synthesis induced by prostaglandin E2: cross-talk regulation by protein kinase C

Bone. 1998 Apr;22(4):355-60. doi: 10.1016/s8756-3282(97)00293-7.


We previously showed that prostaglandin E2 (PGE2) stimulates multiple intracellular signaling pathways as follows: by activation of adenylate cyclase; phosphoinositide (PI)-hydrolyzing phospholipase C and phosphatidylcholine (PC)-hydrolyzing phospholipase D; and by induction of Ca2+ influx in osteoblast-like MC3T3-E1 cells. In this study, we investigated the effect of PGE2 on the synthesis of interleukin-6 (IL-6) and its regulatory mechanism in MC3T3-E1 cells. PGE2 significantly stimulated IL-6 secretion in a dose-dependent manner in the range between 1 nmol/L and 10 micromol/L. A23187, a calcium ionophore, or dibutyryl-cAMP significantly induced IL-6 secretion. The effect of a combination of A23187 and dibutyryl-cAMP on IL-6 secretion was additive. The depletion of extracellular Ca2+ by EGTA reduced the PGE2-induced IL-6 secretion. EP1 receptor antagonist inhibited the PGE2-induced IL-6 secretion. H-89, an inhibitor of cAMP-dependent protein kinase, decreased the PGE2-induced IL-6 secretion. EP2 receptor agonist alone stimulated IL-6 secretion. However, EP4 receptor antagonist had little effect on IL-6 secretion. Calphostin C, a specific inhibitor of protein kinase C (PKC), enhanced the secretion of IL-6 induced by PGE2. The stimulative effect of PGE2 on IL-6 secretion was significantly enhanced in PKC downregulated MC3T3-E1 cells. Pertussis toxin enhanced PGE2-induced IL-6 secretion. These results strongly suggest that PGE2 stimulates IL-6 synthesis through both Ca2+ mobilization from extracellular space via EP1 receptor and cAMP production via EP2 receptor in osteoblast-like cells, and that the PKC activation by PGE2 itself regulates oversynthesis of IL-6.

MeSH terms

  • 3T3 Cells
  • Animals
  • Bucladesine / pharmacology
  • Calcimycin / pharmacology
  • Calcium / metabolism
  • Chelating Agents / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Dinoprostone / pharmacology*
  • Dose-Response Relationship, Drug
  • Egtazic Acid / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Interleukin-6 / biosynthesis*
  • Ionophores / pharmacology
  • Isoquinolines / pharmacology
  • Mice
  • Naphthalenes / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Receptors, Prostaglandin E / agonists
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Prostaglandin E, EP2 Subtype
  • Sulfonamides*


  • Chelating Agents
  • Enzyme Inhibitors
  • Interleukin-6
  • Ionophores
  • Isoquinolines
  • Naphthalenes
  • Ptger2 protein, mouse
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP2 Subtype
  • Sulfonamides
  • Calcimycin
  • Egtazic Acid
  • Bucladesine
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • calphostin C
  • Dinoprostone
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Calcium