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Tumour necrosis factor alpha‐induced oxidative burst in neutrophils adherent to fibronectin: effects of cyclic AMP‐elevating agents
Author(s) -
Ottonello L.,
Morone M. P.,
Dapino P.,
Dallegri F.
Publication year - 1995
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1995.tb05348.x
Subject(s) - respiratory burst , fibronectin , necrosis , tumor necrosis factor alpha , medicine , oxidative phosphorylation , alpha (finance) , cancer research , immunology , pharmacology , chemistry , biochemistry , cell , surgery , construct validity , patient satisfaction
Summary. Human neutrophils, plated on flbronectin‐coated polystyrene wells, were found to exhibit a prolonged production of superoxide anion (O − 2 ) in response to tumour necrosis factor‐alpha (TNF). The TNF‐triggered O − 2 production was significantly reduced by 10μM prostaglandin E 2 (PGE 2 ), which was ineffective at lower doses. Moreover, the O − 2 production was slightly reduced by the phosphodiesterase type IV (PDEIV) inhibitor RO 20‐1724. When PGE 2 and RO 20‐1724 were added together to TNF‐triggered neutrophils they caused a marked synergistic inhibition of O − 2 production. The action of PGE 2 could be mimicked by forskolin (FK), a well‐known direct activator of adenylate cyclase. These results suggest that cyclic AMP (cAMP)‐elevating agents (PGE 2 , FK, RO 20‐1724) down‐regulate the capacity of adherent neutrophils to mount the respiratory burst in response to TNF. Consistent with this interpretation, PGE 2 and RO 20‐1724 increased the intracellular levels of cAMP displaying synergistic activity. Moreover, the membrane‐permeable analogue of cAMP, dibutyryl cAMP, was found to inhibit the TNF‐induced O − 2 production in a dose‐dependent manner. As all the aforementioned cAMP‐elevating agents did not affect the O − 2 production in response to phorbol myristate acetate, they appear to act by interfering with the assembly of the O − 2 ‐generating NADPH oxidase complex rather than by directly inhibiting the activity of already working oxidase complex. In conclusion, taking into account the TNF capacity to promote PGE 2 formation at sites of inflammation, our observations suggest the existence of a negative PGE 2 ‐dependent feed‐back, potentially capable of controlling the neutrophil response to TNF and susceptible to amplification by PDE IV‐inhibiting compounds.