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

O. Kozawa, Atsushi Suzuki, H. Tokuda, T. Kaida, T. Uematsu

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

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 μmol/L. A23187, a calcium ionophore, or dibutyrgl-cAMP significantly induced IL-6 secretion. The effect of a combination of A23187 and dihutyryl-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.

Original languageEnglish
Pages (from-to)355-360
Number of pages6
JournalBone
Volume22
Issue number4
DOIs
Publication statusPublished - 01-04-1998

Fingerprint

Dinoprostone
Protein Kinase C
Interleukin-6
Calcimycin
Osteoblasts
Cyclic AMP Receptors
Phosphoinositide Phospholipase C
Phospholipase D
Calcium Ionophores
Egtazic Acid
Pertussis Toxin
Extracellular Space
Cyclic AMP-Dependent Protein Kinases
Phosphatidylcholines
Adenylyl Cyclases
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Kozawa, O. ; Suzuki, Atsushi ; Tokuda, H. ; Kaida, T. ; Uematsu, T. / Interleukin-6 synthesis induced by prostaglandin E2 : Cross-talk regulation by protein kinase C. In: Bone. 1998 ; Vol. 22, No. 4. pp. 355-360.
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Interleukin-6 synthesis induced by prostaglandin E2 : Cross-talk regulation by protein kinase C. / Kozawa, O.; Suzuki, Atsushi; Tokuda, H.; Kaida, T.; Uematsu, T.

In: Bone, Vol. 22, No. 4, 01.04.1998, p. 355-360.

Research output: Contribution to journalArticle

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T1 - Interleukin-6 synthesis induced by prostaglandin E2

T2 - Cross-talk regulation by protein kinase C

AU - Kozawa, O.

AU - Suzuki, Atsushi

AU - Tokuda, H.

AU - Kaida, T.

AU - Uematsu, T.

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AB - 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 μmol/L. A23187, a calcium ionophore, or dibutyrgl-cAMP significantly induced IL-6 secretion. The effect of a combination of A23187 and dihutyryl-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.

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