Transmethylation reactions are required for initial morphologic and biochemical responses of human monocytes to chemoattractants.

Transmethylation reactions mediated by S-adenosyl-L-methionine are required for the chemotaxis of mononuclear leukocytes. It is not yet known, however, whether methylation reactions participate in the initial transduction of the chemotactic signals that lead to the alterations in cellular morphology required for chemotaxis and/or whether they are necessary for the subsequent biochemical events needed for sustained directed migration. We therefore investigated the effects of inhibiting methylation on 2 early responses induced by chemoattractant-receptor occupancy in human monocytes; the rapid morphologic alteration from round to a triangular, motile cell configuration (polarization) and the release of [3H]-arachidonic acid from membrane phospholipids. Both of these initial responses to 3 types of chemoattractants were severely depressed in monocytes treated with the methylation inhibitors, erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA) plus adenosine and L-homocysteine or by 3-deazaadenosine plus L-homocysteine. These findings indicate that methylation reactions are required for the transduction of signals after chemotactic factor receptor occupancy in monocytes, which lead to a motile cellular configuration and release of arachidonic acid from membrane phospholipids. Activation of phospholipases with destruction of cell-associated phosphatidylinositol appears to account for the major source of arachidonic acid released by monocytes exposed to chemoattractants. This pathway for arachidonic acid release requires a transmethylation reaction since it is blocked by inhibitors of methylation.