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 inflamma tory reactions and may then act on mast cells. In the present work, we attempted to clarify the role of this molecule on the proliferation a nd IgE-mediated activation of mouse bone-marrow-derived mast cells obt ained by culture in the presence of IL-3 (BMMC). Treatment of BMMC wit h increasing concentrations of sodium nitroprusside (SNP) induced a do se-dependent inhibition of H-3-thymidine incorporation (IC50=50 mu M) without affecting cell survival under 100 mu M. Furthermore, nitric ox ide dramatically decreased beta-hexosaminidase and TNF-alpha release i nduced by Fc epsilon RI ligation on BMMC (respectively 45 and 57% for 100 mu M). These inhibitory effects are mediated at least in part thro ugh enhancement of intracellular cyclic nucleotides levels since: 1) i ntracellular cGMP and cAMP levels increased within minutes after NO tr eatment, 2) treatment of BMMC with a cAMP analogue induced antiprolife rative effect on BMMC and 3) pretreatment of BMMC with a cAMP antagoni st partly reversed the inhibitory activity of SNP. (C) Academic Press, Inc.