HETEROGENEOUS SPONTANEOUS AND INTERLEUKIN-4-INDUCED NITRIC-OXIDE PRODUCTION BY HUMAN MONOCYTES

The generation of nitric oxide by human monocytes has long been a subj ect of controversy because of the difficulty of rationalizing this pro duction. In this work we evaluated the capacity of human monocytes to produce nitric oxide (NO) as measured by nitrite (NO2-) release. Resti ng unstimulated monocytes (2 x 10(6) cells/ml) were found to produce s ignificant amounts of NO2- after 8 to 12 days in culture. This product ion appeared to be highly heterogeneous. Indeed, approximately, 75% of monocytes from the different donors produced up to 10 mu M NO2- and w ere considered low producers; the last 25% produced higher amounts of NO2- (from 10 to 110 mu M) and were considered high producers. In any case the spontaneous production of NO2- by monocytes was overcome in t he presence of 1 mM N-omega-monomethyl-L-arginine (LNMMA). This inhibi tory effect was reversed in the presence of an excess of L-arginine (5 mM), indicating that this process is effectively dependent on L-argin ine metabolism. Because interleukin-4 (IL-4) is considered an importan t NO-regulatory cytokine, its regulatory effect on this spontaneous pr oduction of NO was also evaluated. In the presence of a defined dose o f IL-4 (1 to 100 ng/ml) the spontaneous production of the high-produci ng population of monocytes was abrogated, whereas IL-4 stimulated the production by the low-producing population of monocytes, which was sup pressed in the presence of LNMMA. The present data indicate that NO pr oduction by human monocytes is heterogeneous and that IL-4 can be a po tent inducer or inhibitor of this production, suggesting a variability in the activation state of these cells.