期刊
BIOCHEMICAL PHARMACOLOGY
卷 78, 期 4, 页码 396-405出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2009.04.030
关键词
cAMP; Eosinophil; Apoptosis; Inflammation; Akt; NF-kappa B
资金
- European Union FP6 [L-SHB-CF-2005-518167]
- Fundaca de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- MRC [G0601481] Funding Source: UKRI
- Medical Research Council [G0601481, G9900991B] Funding Source: researchfish
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 24 h and persisted till 48 h. Treatment with the PDE4 inhibitor rolipram, cAMP mimetic db-cAMP or adenylate cyclase activator forskolin, at 24 h 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 P13K/Akt or NF-kappa B induced resolution of inflammation that was associated with increased apoptosis. OVA-challenge resulted in a time-dependent activation of Akt and NF-kappa B, which was blocked by treatment with rolipram or P13K/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-kappa B survival pathway. (C) 2009 Elsevier Inc. All rights reserved.
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