Cyclic AMP enhances resolution of allergic pleurisy by promoting inflammatory cell apoptosis via inhibition of PI3K/Akt and NF-kappaB.
Selective and timely induction of apoptosis is an effective means of resolving inflammation. The effects and putative mechanisms by which cyclic AMP (cAMP) modulates leukocyte apoptosis in vivo are still unclear. The present study aims at identifying intracellular pathways underlying the ability of cAMP elevating agents to resolve eosinophilic inflammation in a model of allergic pleurisy in mice. Ovalbumin (OVA) challenge of immunized mice induced eosinophil recruitment that peaked at 24h and persisted till 48h. Treatment with the PDE4 inhibitor rolipram, cAMP mimetic db-cAMP or adenylate cyclase activator forskolin, at 24h after antigen-challenge resulted in profound resolution of eosinophilic inflammation, without a decrease of mononuclear cell numbers. There was a concomitant increase in number of apoptotic cells in the pleural cavity. The effects of rolipram and db-cAMP were inhibited by the PKA inhibitor H89. Inhibition of PI3K/Akt or NF-kappaB induced resolution of inflammation that was associated with increased apoptosis. OVA-challenge resulted in a time-dependent activation of Akt and NF-kappaB, which was blocked by treatment with rolipram or PI3K/Akt pathway inhibitors. Thus, cAMP elevating agents resolve established eosinophilic inflammation by inducing leukocyte apoptosis. Mechanistically, the actions of cAMP are dependent on PKA and target a PI3K/Akt-dependent NF-kappaB survival pathway.
Setor de Patologia Clínica, Colégio Técnico, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Lirlândia P
LP
Sousa
Aline F
AF
Carmo
Bárbara M
BM
Rezende
Fernando
F
Lopes
Douglas M
DM
Silva
Ana L
AL
Alessandri
Cláudio A
CA
Bonjardim
Adriano G
AG
Rossi
Mauro M
MM
Teixeira
Vanessa
V
Pinho
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000009:adverse effects*; D004804:Eosinophils / Q000502:physiology*; D006967:Hypersensitivity / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010998:Pleurisy / Q000139:chemically induced*
D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000242:Cyclic AMP