CYCLIC NUCLEOTIDES CONTROL DIFFERENTIATION OF HUMAN MONOCYTES INTO EITHER HIGHLY ACCESSORY CELLS OR MACROPHAGES

Human peripheral blood monocytes have been found to undergo a transitory state of high accessory activity before they fully become macrophages. Time kinetics were done to follow this accessory potential. Studying the regulation of accessory activity, we have found that monocyte derived accessory cells (m-AC) pass through two phases of development, both of which are adversely controlled by cyclic nucleotides. Phase I is positively correlated by intracellular cAMP increase and can be blocked by increase of cGMP, whereas phase II positively correlates with increase of intracellular cGMP and can be completel y blocked by cAMP and synergystic agents. In addition to cAMP, non-cyclic adenine nucleotides and adenosine also mimic all cAMP effects. This behavior is explained by the known presence of surface 5- nucleotidase and adenosine receptors which in turn leads to activation of adenyl ate cyclase. At phase II, serum is required to convert m-AC into macrophages. In the absence of serum, cells were arrested in the m-AC state. Adenine nucleotides effectively counteract serum induction, leading to the development of m-AC even in the presence of serum. Monocyte/macrophage markers such as Fc receptors and nonspecific esterase strictly correlate negatively with the expression of accessory activity, whereas morphologically the appearance of veils positively correlates with all experimental situations of high accessory activity. Therefore, it is evident that serum contains regulatory factors that strongly modify the accessory potency of the m-AC via the cyclic nucleotide system, thus presenting a new immunoregulatory principle at the beginning of the immune cascade.