CAMP ANALOGS DOWN-REGULATE THE EXPRESSION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) IN HUMAN BONE-MARROW STROMAL CELLS IN-VITRO

THE stimulation of granulocyte macrophage-colony stimulating factor (G M-CSF) by interleukin-1 (IL-1) has been shown to be counteracted in di fferent mesenchymal cell systems by cyclic adenosine monophosphate (cA MP) agonists. The aim of this study was the evaluation of different cA MP agonists on GM-CSF expression in human bone marrow stromal cells. I ncubation of secondary haematopoietic progenitor cell deprived human s tromal cell cultures with IL-1 or TNF-alpha induced GM-CSF protein exp ression in culture supernatants and GM-CSF-mRNA in adherent stromal ce lls. The coincubation with 8-bromo-cAMP (8BrcAMP), a water soluble cAM P analogue, inhibited this GM-CSF stimulation at the protein and the m RNA level, This effect was dose dependent with a maximal inhibition of about 65% occurring at a 8BrcAMP concentration of 0.75 mM, In additio n to 8BrcAMP, other cAMP agonists such as dibutyryl-cAMP, forskolin, p ertussis toxin, or prostaglandin E-2 (PGE(2)) had the same inhibitory effect on GM-CSF stimulation by IL-1. Coincubation with the cyclooxyge nase inhibitor indomethacin had no significant influence on GM-CSF exp ression in stromal cells. Our results provide evidence that the previo usly described inhibitory effect of cAMP agonist PGE(2) on haematopoie tic progenitor cells in vivo is, at least in part, mediated by modulat ing the expression of GM-CSF in bone marrow stromal cells.