PKA-dependent activation of PKC, p38 MAPK and IKK in macrophage: implication in the induction of inducible nitric oxide synthase and interleukin-6 by dibutyryl cAMP

Cell Signal. 2004 May;16(5):565-75. doi: 10.1016/j.cellsig.2003.10.003.

Abstract

In this study, we examined the signal transduction of dibutyryl cyclic adenosine monophosphate (dBcAMP) to stimulate the release of nitric oxide (NO) and interleukin-6 (IL-6) from J774 macrophages. These actions of dBcAMP were diminished by the presence of the inhibitors of protein kinase A (PKA), protein kinase C (PKC), p38 MAPK and nuclear factor-kappa B (NF-kappaB). In contrast, Go 6976 and PD98059 had no significant effects. Consistently, dBcAMP caused membrane translocation of PKCbetaII, delta, mu, lambda and zeta isoforms, and increased atypical protein kinase C (aPKC) and p38 MAPK activities. The nuclear translocation and DNA-binding study revealed that dBcAMP stimulated NF-kappaB, activator protein-1 (AP-1), and CAAT/enhancer-binding protein (c/EBPbeta). Via PKA, PKC and p38 MAPK-dependent signals, dBcAMP also induced inhibitory subunit of NF-kappaB (IkappaB) degradation, IkappaB kinase (IKK) activation, nuclear translocation of NF-kappaB subunit p65 and its association with the CREB-binding protein (CBP). These results illustrate that PKA activation in macrophages is able to stimulate PKC and p38 MAPK, which lead to IKK-dependent NF-kappaB activation and contribute to the induction of inducible nitric oxide synthase (iNOS) and IL-6 genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bucladesine / pharmacology*
  • Carbazoles / pharmacology
  • Carrier Proteins / pharmacology
  • Cell Line
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • I-kappa B Kinase
  • Indoles / pharmacology
  • Interleukin-6 / biosynthesis*
  • Intracellular Signaling Peptides and Proteins*
  • Macrophages / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / biosynthesis*
  • Nitric Oxide Synthase Type II
  • Phosphorylation / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction* / drug effects
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Carbazoles
  • Carrier Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Indoles
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • protein kinase modulator
  • Go 6976
  • Bucladesine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Protein Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one