cAMP protects neutrophils against TNF-alpha-induced apoptosis by activation of cAMP-dependent protein kinase, independently of exchange protein directly activated by cAMP (Epac).

Abstract

It is unclear by which receptor cyclic adenosine monophosphate (cAMP) acts to promote neutrophil survival. We found that 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, a specific activator of the recently discovered cAMP receptor, cAMP-regulated guanosine 5'-triphosphate exchange protein directly activated by cAMP, failed to protect human neutrophils from cell death. In contrast, specific activators of cAMP-dependent protein kinase type I (cA-PKI) could protect against death receptor [tumor necrosis factor receptor 1 (TNFR-1), Fas]-mediated apoptosis as well as cycloheximide-accelerated "spontaneous" apoptosis. A novel "caged" cA-PK-activating analog, 8-bromo (8-Br)-acetoxymethyl-cAMP, was more than 20-fold more potent than 8-Br-cAMP to protect neutrophils challenged with TNF-alpha against apoptosis. This analog acted more rapidly than forskolin (which increases the endogenous cAMP production) and allowed us to demonstrate that cA-PK must be activated during the first 10 min after TNF-alpha challenge to protect against apoptosis. The protective effect was mediated solely through cA-PK activation, as it was abolished by the cA-PKI-directed inhibitor Rp-8-Br-cAMPS and the general cA-PK inhibitor H-89. Neutrophils not stimulated by cAMP-elevating agents showed increased apoptosis when exposed to the cA-PK inhibitors Rp-8-Br-cAMPS and H-89, suggesting that even moderate activation of cA-PK is sufficient to enhance neutrophil longevity and thereby contribute to neutrophil accumulation in chronic inflammation.

• Authors: Camilla Krakstad, Anne Elisabeth Christensen, Stein Ove Døskeland
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 76 Issue 3 Pg. 641-7 (Sep 2004) ISSN: 0741-5400 [Print] United States
• PMID: 15178699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Enzyme Inhibitors
• Guanine Nucleotide Exchange Factors
• RAPGEF3 protein, human
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• Tumor Necrosis Factor-alpha
• Colforsin
• 8-Bromo Cyclic Adenosine Monophosphate
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (pharmacology)
• Antigens, CD (drug effects, metabolism)
• Apoptosis (drug effects, immunology)
• Cell Survival (drug effects, immunology)
• Cells, Cultured
• Chemotaxis, Leukocyte (drug effects, immunology)
• Colforsin (pharmacology)
• Cyclic AMP (analogs & derivatives, metabolism, pharmacology)
• Cyclic AMP-Dependent Protein Kinases (drug effects, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Guanine Nucleotide Exchange Factors (drug effects, metabolism)
• Humans
• Inflammation (enzymology, immunology)
• Neutrophils (drug effects, enzymology, immunology)
• Receptors, Tumor Necrosis Factor (drug effects, metabolism)
• Receptors, Tumor Necrosis Factor, Type I
• Tumor Necrosis Factor-alpha (immunology, metabolism, pharmacology)