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

• Published in: Bone (New York, N.Y.) Vol. 22; no. 4; pp. 355 - 360
• Main Authors: KOZAWA, O, SUZUKI, A, TOKUDA, H, KAIDA, T, UEMATSU, T
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Science 01.04.1998
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; 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; Fundamental and applied biological sciences. Psychology; 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; Skeleton and joints; Sulfonamides; Vertebrates: osteoarticular system, musculoskeletal system; Cell culture; Protein kinase C; Calcium; Prostaglandin; Enzyme; Arachidonic acid derivatives; Transferases; Cytokine; Rodentia; Cyclic AMP; Prostaglandin E2; Metabolism; In vitro; Interleukin 6; Vertebrata; Regulation(control); Mammalia; Mouse; Animal; Bone; Quantitative analysis
• ISSN: 8756-3282; 1873-2763
• 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.