INTERLEUKIN-4 STIMULATES CGMP PRODUCTION BY IFN-GAMMA-ACTIVATED HUMANMONOCYTES - INVOLVEMENT OF THE NITRIC-OXIDE SYNTHASE PATHWAY

Resting human blood monocytes from some donors were found to produce a small amount of 3'-5' guanine cyclic monophosphate (CGMP) in response to interleukin 4 (IL-4). A much higher response was observed when mon ocytes were preincubated with interferon (IFN-gamma), which alone was ineffective. Preincubation of monocytes with IL-4 led, in contrast, to their subsequent incapacity to generate cGMP in response to IL-4. The accumulation of cGMP induced by IL-4 in IFN-gamma preincubated monocy tes was dose-dependent and peaked about 15 min after its addition. It was inhibited in the presence of N(G)-mono-methyl-L-arginine (L-NMMA), an inhibitor of the nitric oxide synthase pathway. This suppressive e ffect Of L-NMMA was reverted by an excess Of L- but not of D-arginine. Accumulation of cGMP was significantly reduced by addition of soluble guanylyl cyclase inhibitors, such as LY83853 and methylene blue, but was not impaired in the presence of EGTA, suggesting that the pathway involved is calcium independent. In addition, IL-4 induced an increase d secretion of nitrite by monocytes, that was potentiated by IFN-gamma and inhibited by L-NMMA. Taken together, these results suggest that t he sequential exposure of monocytes to IFN-gamma and IL-4 elicits the release of NO from L-arginine, which in turn is capable to stimulate s oluble guanylyl cyclase.