A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils.
The glucocorticoid-inducible protein annexin (ANXA) 1 is an anti-inflammatory mediator that down-regulates the host response. Endogenously, ANXA1 is released in large amounts from adherent polymorphonuclear neutrophils (PMN) and binds to their cell surface to inhibit their extravasation into inflamed tissues. The present study determined the effects of exogenous ANXA1 on several functions of human PMN in vitro. Addition of 0.1-1 microM human recombinant ANXA1 to the PMN provoked rapid and transient changes in intracellular Ca2+ concentrations that were blocked by the Ca2+ channel inhibitor SKF-96365. Although ANXA1 did not affect oxidant production and only minimally affected PMN chemotactic properties, the ANXA1-promoted Ca2+ influx was associated with two important functional effects: shedding of L-selectin and acceleration of PMN apoptosis. The latter effect was confirmed using three distinct technical procedures, namely, cell cycle, Hoechst staining, and ANXA5 binding assay. ANXA1-induced PMN apoptosis was insensitive to inhibitors of L-selectin shedding, whereas it appeared to be associated with dephosphorylation of the proapoptotic intracellular mediator BAD. In conclusion, exogenous ANXA1 displayed selective actions on human PMN. We propose that the new proapoptotic effect reported here may be part of the spectrum of ANXA1-mediated events involved in the resolution of acute inflammation.
Solito
Egle
E
Department of Neuroendocrinology, Imperial College London, Hammersmith Campus, Commonwealth Building, Du Cane Rd., London W12 ONN, London, UK. E-mail: e.solito@ic.ac.uk
Kamal
Ahmad
A
Russo-Marie
Francoise
F
Buckingham
Julia C
JC
Marullo
Stefano
S
Perretti
Mauro
M
D017305:Annexin A1 / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008954:Models, Biological; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
D017305:Annexin A1; D002121:Calcium Channel Blockers; D007093:Imidazoles; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium