The ceramide-1-phosphate analogue PCERA-1 modulates tumour necrosis factor-alpha and interleukin-10 production in macrophages via the cAMP-PKA-CREB pathway in a GTP-dependent manner

Autor: Dorit Avni, Tsaffrir Zor, Michael M. Meijler, Amir Philosoph
Rok vydání: 2009
Předmět:
Lipopolysaccharides
Indoles
Pyridines
medicine.medical_treatment
p38 Mitogen-Activated Protein Kinases
chemistry.chemical_compound
Mice
Genes
Reporter
Cyclic AMP
Immunology and Allergy
Enzyme Inhibitors
Phosphorylation
Cyclic AMP Response Element-Binding Protein
Sulfonamides
Anti-Inflammatory Agents
Non-Steroidal
Imidazoles
Phosphodiesterase
Cell biology
Interleukin-10
Interleukin 10
Cytokine
Biochemistry
Guanosine Triphosphate
Rolipram
medicine.drug
Adenylyl Cyclases
Signal Transduction
Immunology
Biology
CREB
Ceramides
Response Elements
Transfection
Ribosomal Protein S6 Kinases
90-kDa
Dinoprostone
Cell Line
medicine
Animals
Cyclic adenosine monophosphate
Calcium Signaling
Protein kinase A
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
Macrophages
Cell Membrane
Original Articles
Isoquinolines
Cyclic AMP-Dependent Protein Kinases
chemistry
Bucladesine
biology.protein
Zdroj: Immunology. 129(3)
ISSN: 1365-2567
Popis: The synthetic phospho-ceramide analogue-1 (PCERA-1) down-regulates production of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) and up-regulates production of the anti-inflammatory cytokine interleukin-10 (IL-10) in lipopolysaccharide (LPS) -stimulated macrophages. We have previously reported that PCERA-1 increases cyclic adenosine monophosphate (cAMP) levels. The objective of this study was to delineate the signalling pathway leading from PCERA-1 via cAMP to modulation of TNF-alpha and IL-10 production. We show here that PCERA-1 elevates intra-cellular cAMP level in a guanosine triphosphate-dependent manner in RAW264.7 macrophages. The cell-permeable dibutyryl cAMP was able to mimic the effects of PCERA-1 on cytokine production, whereas 8-chloro-phenylthio-methyladenosine-cAMP, which specifically activates the exchange protein directly activated by cAMP (EPAC) but not protein kinase A (PKA), failed to mimic PCERA-1 activities. Consistently, the PKA inhibitor H89 efficiently blocked PCERA-1-driven cytokine modulation as well as PCERA-1-stimulated phosphorylation of cAMP response element binding protein (CREB) on Ser-133. Finally, PCERA-1 activated cAMP-responsive transcription of a luciferase reporter, in synergism with the phosphodiesterase (PDE)-4 inhibitor rolipram. Our results suggest that PCERA-1 activates a G(s) protein-coupled receptor, leading to elevation of cAMP, which acts via the PKA-CREB pathway to promote TNF-alpha suppression and IL-10 induction in LPS-stimulated macrophages. Identification of the PCERA-1 receptor is expected to set up a new target for development of novel anti-inflammatory drugs.
Databáze: OpenAIRE
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