Effects of granulocyte-macrophage colony-stimulating factor and cyclic AMP interaction on human neutrophil apoptosis.

Cosimo Tortorella,Giuseppina Piazzolla,Salvatore Antonaci,Felice Spaccavento

doi:10.1080/09629359890767

Abstract

The current study was undertaken to evaluate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclic AMP (cAMP) signaling interaction on human neutrophil apoptosis, either occurring spontaneously or induced by Fas antigen activation. Results show that GM-CSF, dibutyryl cAMP (a cAMP analog) and forskolin (an adenylate cyclase activator) are all able to suppress spontaneous neutrophil cell death. Of note however, when GM-CSF is used in combination with cAMP-elevating agents, an additive effect on neutrophil survival is observed with dibutyryl cAMP only, whereas supplementation of cell cultures with GM-CSF and forskolin results in a progressive reduction of antiapoptotic effects exerted by the single compounds. Moreover, although dibutyryl cAMP and forskolin do not affect Fas-triggered apoptotic events, they are still able to modulate the GM-CSF capacity to prolong neutrophil survival following anti-Fas IgM cell challenge, with effects similar to those respectively exerted on spontaneous neutrophil apoptosis. The data indicate that GM-CSF may negatively modulate the cAMP-mediated antiapoptotic pathway in human neutrophils, likely via the inhibition of adenylate cyclase activity. This would prevent an abnormal neutrophil survival as a result of cAMP signaling stimulation, which provides a novel insight into the role of GM-CSF as a physiological regulator of myeloid cell turnover.

Highlights

Polymorphonuclear le ukoc ytes (PMN) play a critic al role in host de fens e against invading mic roorganisms,[1] as w ell as in local and syste mic inflammatory diseases.[2]
Sinc e mature ne utrophils are te rminally diffe re ntiate d ce lls incapable of self-re ne w al,[3] such an e ve nt is made possible by a continuous highly c ontrolled balanc e be tw e en the entry of ne w born cells into the blood and the e limination of sene sce nt PMN in the tissue s
Of note how e ver is that both cAMP-ele vating agents p rove to be e ffec tive in modulating the antia poptotic ac tivity of GM-CSF, w ith dibutyryl cAMP e nhancing and forskolin inhibitin g the c ytokine c apacity to prolong PMN survival follow ing anti-Fas IgMmAb c ell challenge (Fig. 3)

Summary

Introduction

Polymorphonuclear le ukoc ytes (PMN) play a critic al role in host de fens e against invading mic roorganisms,[1] as w ell as in local and syste mic inflammatory diseases.[2]. Ne utrophils appe ar to be committed to apoptotic c ell death in vivo as w ell as in v itro , this proce ss is susce ptible to modulation by diffe re nt compounds In this contex t, it has be e n re ported that Fas antige n engage ment on the PMN surface , either by Fas ligand binding or binding of agonistic anti-Fas IgM antibody, marke dly acc elerate s ne utrophil ap optosis.[10,11] On the c ontrary, many PMN ac tivators, including proinflammatory cytokines and bacte rial products are all able to p rolong the life span and the functional ac tivity of PMN in vitro .4,10 –14. CAMP analog) or forskolin (an ade nylate cyclase activator), used alone or in combination w ith GM-CSF, have be en supplemente d to PMN ce ll cultures, and the occurrenc e of apoptosis, either spontaneous or induc ed by Fas antigen ac tivation, has be en evaluate d on the basis of typic al morphological change s as w e ll as quantitative assay of DNA fragme ntation

Materials and Methods

Results

Discussion