Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation.

Abstract

Alveolar macrophages (AMs) represent the first line of innate immune defense in the lung. AMs use pattern recognition receptors (PRRs) to sense pathogens. The best studied PRR is Toll-like receptor (TLR)4, which detects LPS from gram-negative bacteria. The lipid mediator prostaglandin (PG)E2 dampens AM immune responses by inhibiting the signaling events downstream of PRRs. We examined the effect of PGE2 on TLR4 expression in rat AMs. Although PGE2 did not reduce the mRNA levels of TLR4, it decreased TLR4 protein levels. The translation inhibitor cycloheximide reduced TLR4 protein levels with similar kinetics as PGE2, and its effects were not additive with those of the prostanoid, suggesting that PGE2 inhibits TLR at the translational level. The action of PGE2 could be mimicked by the direct stimulator of cAMP formation, forskolin, and involved E prostanoid receptor 2 ligation and cAMP-dependent activation of unanchored type I protein kinase A. Cells pretreated with PGE2 for 24 hours exhibited decreased TNF-α mRNA and protein levels in response to LPS stimulation. Knockdown of TLR4 protein by small interfering RNA to the levels achieved by PGE2 treatment likewise decreased TNF-α mRNA and protein in response to LPS, establishing the functional significance of this PGE2 effect. We provide the first evidence of a lipid mediator acting through its cognate G protein-coupled receptor to affect PRR translation. Because PGE2 is produced in abundance at sites of infection, its inhibitory effects on AM TLR4 expression have important implications for host defense in the lung.

• Authors: Angela Juliette Degraaf, Zbigniew Zasłona, Emilie Bourdonnay, Marc Peters-Golden
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 51 Issue 2 Pg. 242-50 (Aug 2014) ISSN: 1535-4989 [Electronic] United States
• PMID: 24601788 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• RNA, Messenger
• Receptors, Prostaglandin E
• TLR4 protein, human
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinase Type I
• Adenylyl Cyclases
• Dinoprostone

Topics

• Adenylyl Cyclases (metabolism)
• Animals
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinase Type I (metabolism)
• Dinoprostone (metabolism)
• Down-Regulation
• Female
• Humans
• Immunity, Innate
• Inflammation Mediators (metabolism)
• Macrophages, Alveolar (immunology, metabolism)
• RNA Interference
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Receptors, Prostaglandin E (metabolism)
• Signal Transduction
• Time Factors
• Toll-Like Receptor 4 (genetics, metabolism)
• Transcription, Genetic
• Transfection
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• U937 Cells