Two new formylated peptides able to activate chemotaxis and respiratory burst selectively as tools for studying human neutrophil responses

Two new For-Met-Leu-Phe-OH (FMLP) methyl ester analogues, For-Thp-Leu-Ain-OMe [Thp 1, Ain 3] and For-Met- Δ zLeu-Phe-OMe [ Δ zLeu 2], able to activate selectively chemotaxis and superoxide anion (O 2 −) release, respectively modulate intracellular cyclic AMP (cAMP) levels in different ways. FMLP and [ Δ zLeu 2] enhance human neutrophil cAMP levels per se, and this effect is potentiated by Ro 201724, a non-xanthinic phosphodiesterase (PDE) inhibitor, whereas it is counteracted by 3-isobutyl-1-methyl-xanthine (IBMX), a blocker of both phosphodiesterase and adenosine receptors. In contrast, [Thp 1, Ain 3] is ineffective. However, no formylated peptides influence cAMP phosphodisterase activity. Neutropil preincubation with Ro 201724 or IBMX drastically reduces chemotaxis and superoxide anion (O 2 −) production triggered by peptides. Our results suggest that: (1) peptide-induced cAMP increase is probably indirect, and due mainly to the action on adenosine-sensitive adenylate cyclase; (2) formylated peptide, endowed solely with chemotactic activity is unable to increase neutrophil cAMP concentration; (3) cAMP elevation may represent a feed-back mechanism to inhibit the physiological responses induced by formylated peptides.