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J Biol Chem. 2017 Aug 18;292(33):13758-13773. doi: 10.1074/jbc.M117.800391. Epub 2017 Jun 27.

The resolution of acute inflammation induced by cyclic AMP is dependent on annexin A1.

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From the Programa de Pós-Graduação em Biologia Celular, Departamento de Morfologia, Instituto de Ciências Biológicas.
the Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia.
the Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, and.
the Departamento de Biologia Geral, Genética, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Pampulha 31270-901, Belo Horizonte, Brazil and.
the William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
From the Programa de Pós-Graduação em Biologia Celular, Departamento de Morfologia, Instituto de Ciências Biológicas,


Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti-inflammatory and pro-resolving effects. We have shown previously that the cAMP-enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow-up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by using N-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drugs.


annexin; apoptosis; cyclic AMP (cAMP); inflammation; neutrophil; protein kinase A (PKA)

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