Allergy Asthma Immunol Res.
2013 Sep;5(5):329-336. 10.4168/aair.2013.5.5.329.
Suppression of Heme Oxygenase-1 by Prostaglandin E2-Protein Kinase A-A-Kinase Anchoring Protein Signaling Is Central for Augmented Cyclooxygenase-2 Expression in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages
- Affiliations
-
- 1Department of Internal Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul, Korea. ksh1134@eulji.ac.kr
- 2Department of Bio-Medical Laboratory Science, College of Health Science, Eulji University, Suongnam, Korea.
- KMID: 2260815
- DOI: http://doi.org/10.4168/aair.2013.5.5.329
Abstract
- PURPOSE
Prostaglandin (PG) E2 is an immunomodulatory lipid mediator generated mainly via the cyclooxygenase-2 (COX-2) pathway from arachidonic acid at sites of infection and inflammation. A positive feedback loop of PGE2 on COX-2 expression is critical for homeostasis during toll-like receptor (TLR)-mediated inflammatory processes. The mechanism of PGE2-regulated COX-2 expression remains poorly understood. The low-molecular-weight stress protein heme oxygenase-1 (HO-1) contributes to the anti-inflammatory, anti-oxidant and anti-apoptotic response against environmental stress.
METHODS
We explored the involvement of HO-1 on PGE2 regulation of LPS-induced COX-2 expression in RAW 264.7 macrophages.
RESULTS
LPS-induced COX-2 expression in RAW 264.7 macrophages was enhanced by exogenous PGE2 or cyclic AMP (cAMP) analogue and was suppressed by a COX inhibitor (indomethacin), a protein kinase A (PKA) inhibitor (KT5720), and A kinase anchoring protein (AKAP) disruptors (Ht31 and RIAD). This result suggests that the stimulatory effects of endogenous and exogenous PGE2 on COX-2 expression are mediated by a cAMP-PKA-AKAP-dependent pathway. The induction of HO-1 was observed in LPS-stimulated RAW 264.7 macrophages. This induction was suppressed by exogenous PGE2 and enhanced by blockage of the endogenous PGE2 effect by the PKA inhibitor or AKAP disruptors. In addition, HO-1 induction by the HO activator copper protoporphyrin suppressed LPS-induced COX-2 expression, which was restored by the addition of exogenous PGE2. The induction of HO-1 inhibited LPS-induced NF-kappaB p-65 nuclear expression and translocation.
CONCLUSIONS
AKAP plays an important role in PGE2 regulation of COX-2 expression, and the suppression of HO-1 by PGE2-cAMP-PKA-AKAP signaling helps potentiate the LPS-induced COX-2 expression through a positive feedback loop in RAW 264.7 macrophages.
MeSH Terms
-
Arachidonic Acid
Copper
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Cyclooxygenase 2
Dinoprostone
Heme
Heme Oxygenase-1
Homeostasis
Inflammation
Intracellular Signaling Peptides and Proteins
Macrophages
NF-kappa B
Phosphotransferases
Toll-Like Receptors
Arachidonic Acid
Copper
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Cyclooxygenase 2
Dinoprostone
Heme
Heme Oxygenase-1
Intracellular Signaling Peptides and Proteins
NF-kappa B
Phosphotransferases
Toll-Like Receptors
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