The resolution of acute Inflammation induced by cyclic AMP is dependent on annexin A1.
Journal of Biological Chemistry
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Annexin A1 (AnxA1) is a glucocorticoidregulated protein known for its antiinflammatory and proresolving effects. We have previously shown that cAMP enhancing compounds rolipram (ROL - a PDE4 inhibitor) and db-cAMP (cAMP mimetic) drive caspasedependent resolution of neutrophilic inflammation. In this follow up study, we investigated whether AnxA1 could be involved in the proresolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or db-cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices and increased AnxA1 expression. In vitro studies showed that ROL and db-cAMP induced AnxA1 expression and phosphorylation and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA on ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL and db-cAMP-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 BOC-1 a nonselective AnxA1 receptor antagonist or by using an anti-AnxA1 neutralizing antiserum -prevented ROL and db-cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or db-cAMP to induce neutrophil apoptosis was impaired in AnxA knockout mice. Finally, in in vitro settings ROL and db-cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the proresolving properties of cAMP elevating agents and cAMPmimetic drugs.
AuthorsLima, KM; Vago, JP; Caux, TR; Negreiros-Lima, GL; Sugimoto, MA; Tavares, LP; Arribada, RG; Carmo, AAF; Galvão, I; Costa, BRC; Soriani, FM; Pinho, V; Solito, E; Perretti, M; Teixeira, MM; Sousa, LP
- Cardiovascular