INVOLVEMENT OF CYCLIC-NUCLEOTIDES IN THE IMMUNOMODULATORY EFFECTS OF NITRIC-OXIDE ON MURINE MAST-CELLS

Nitric oxide (NO) is synthesized by various cells involved in inflammatory reactions and may then act on mast cells. In the present work, we attempted to clarify the role of this molecule on the proliferation and IgE-mediated activation of mouse bone-marrow-derived mast cells obtained by culture in the presence of IL-3 (BMMC). Treatment of BMMC with increasing concentrations of sodium nitroprusside (SNP) induced a dose-dependent inhibition of H-3-thymidine incorporation (IC50=50 mu M) without affecting cell survival under 100 mu M. Furthermore, nitric oxide dramatically decreased beta-hexosaminidase and TNF-alpha release induced by Fc epsilon RI ligation on BMMC (respectively 45 and 57% for 100 mu M). These inhibitory effects are mediated at least in part through enhancement of intracellular cyclic nucleotides levels since: 1) intracellular cGMP and cAMP levels increased within minutes after NO treatment, 2) treatment of BMMC with a cAMP analogue induced antiproliferative effect on BMMC and 3) pretreatment of BMMC with a cAMP antagonist partly reversed the inhibitory activity of SNP. (C) Academic Press, Inc.