Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 92, Issue 2, Pages 249-258Publisher
WILEY
DOI: 10.1189/jlb.0112008
Keywords
signaling cascade; dexamethasone; wortmannin; rolipram; Bcl-2 family
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Funding
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Pro-Reitoria de Pesquisa da Universidade Federal de Minas Gerais-PRPq (Programa de Auxilio a Pesquisa de Doutores Recem-Contratados)
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This study aimed at assessing whether AnxA1, a downstream mediator for the anti-inflammatory effects of GCs, could affect the fate of immune cells in tissue exudates, using LPS-induced pleurisy in BALB/c mice. AnxA1 protein expression in exudates was increased during natural resolution, as seen at 48-72 h post-LPS, an effect augmented by treatment with GC and associated with marked presence of apoptotic neutrophils in the pleural exudates. The functional relevance of AnxA1 was determined using a neutralizing antibody or a nonspecific antagonist at FPR/ALXRs: either treatment inhibited both spontaneous and GC-induced resolution of inflammation. Injection of Ac2-26 (100 mu g, given 4 h into the LPS response), an AnxA1-active N-terminal peptide, promoted active resolution and augmented the extent of neutrophil apoptosis. Such an effect was prevented by the pan-caspase inhibitor zVAD-fmk. Mechanistically, resolution of neutrophilic inflammation was linked to cell apoptosis with activation of Bax and caspase-3 and inhibition of survival pathways Mcl-1, ERK1/2, and NF-kappa B. These novel in vivo data, using a dynamic model of acute inflammation, provide evidence that AnxA1 is a mediator of natural and GC-induced resolution of inflammation with profound effects on neutrophil apoptosis. J. Leukoc. Biol. 92: 249-258; 2012.
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