Differential inhibition and potentiation of chemoattractant-induced superoxide formation in human neutrophils by the cell-permeant analogue of cyclic GMP, N 2,2′-O-dibutyryl guanosine 3′:5′-cyclic monophosphate

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Abstract
Human neutrophils possess a superoxide (O inf2 sup− )-forming NADPH oxidase which is activated by the chemoattractants, N-formyl-l-methionyl-l-leucyl-l,-phenylalanine (fMet-Leu-Phe), complement C5a, platelet-activating factor and leukotriene B4. We studied the roles of cAMP and cGMP in the regulation of O inf2 sup− formation using the cell-permeant analogues of cyclic nucleotides, N6,2′-O-dibutyryl adenosine 3′:5′-cyclic monophosphate (Bt2cAMP) and N2,2′-O-dibutyryl guanosine 3′:5′-cyclic monophosphate (Bt2cGMP). Bt2cAMP inhibited O inf2 sup− formation induced by these chemoattractants to similar extents. Bt2cGMP as low as 10 μmol/l significantly inhibited O inf2 sup− formation induced by fMet-Leu-Phe at a submaximally effective concentration (50 nmol/1), and Bt2cGMP was more effective in diminishing O inf2 sup− formation than Bt2cAMP. In contrast, Bt2cGMP did not affect O inf2 sup− formation induced by fMet-Leu-Phe at a maximally effective concentration (1 μmol/l). Bt2cGMP (0.1 and 1 mmol/l) enhanced O inf2 sup− formation induced by 0.1 μmol/l C5a by 23% and 49%, respectively, and Bt2cGMP antagonized inhibition of O inf2 sup− formation caused by Bt2cAMP. Bt2cGMP inhibited platelet-activating factor-induced O inf2 sup− formation to a lesser extent than Bt2cAMP and had no effect on that induced by leukotriene B4. Bt2cAMP and Bt2cGMP had no effect on O inf2 sup− formation induced by NaF, γ-hexachlorocyclohexane, phorbol myristate acetate, A 23187 and arachidonic acid. Our data suggest that: 1. Bt2cAMP generally inhibits chemoattractant-stimulated O inf2 sup− formation. 2. Bt2cGMP inhibits fMet-Leu-Phe- and platelet-activating factor-stimulated O inf2 sup− formation but potentiates C5a-induced O inf2 sup− formation. 3. The lack of effect of cyclic nucleotides on O inf2 sup− formation induced by agents other than receptor agonists indicates that cAMP and cGMP modulate early steps of the signal transduction processes initiated by chemoattractants.

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