Cyclic nucleotides regulate the morphologic alterations required for chemotaxis in monocytes.

Abstract

The initial morphologic response of human monocytes to chemoattractants is a change in shape from round to a triangular "motile" configuration (polarization). At doses chemotactic in vitro, chemoattractants induced rapid (t 1/2 = 45 sec), sustained (greater than 40 min) polarization of monocytes in suspension. Extracellular Ca++ was not required for polarization induced by chemoattractants, but in the absence of Ca++ kinetics were slowed (t 1/2 = 6.5 min). Phenylephrine, carbamycholine, serotonin, and ascorbate also caused rapid polarization of monocytes. Unlike chemoattractants, polarization by the pharmacologic agents was unsustained (less than 15 min), absolutely required extracellular Ca++, and affected about 50% of the cells responsive to chemoattractants. Based on relative sensitivities to alpha 1- and alpha 2-adrenergic agonists and antagonists, polarization caused by adrenergic agents was mediated by alpha 2-receptors. Muscarinic and alpha 2-adrenergic agonists, serotonin, and ascorbate enhanced the rate and number of monocytes polarizing to suboptimal doses of chemoattractants. Thus, the initial morphologic changes induced by chemoattractants appear to utilize an activation pathway shared with a variety of agents that enhance cGMP levels and inhibit adenylate cyclase. In contrast, theophylline, histamine, and isoproterenol, all agents that activate adenylate cyclase and elevate cAMP levels, inhibited monocyte polarization to chemoattractants. As in PMN, pharmacologic agents that increase cAMP levels inhibited monocyte chemotaxis in vitro, whereas those that inhibit adenylate cyclase and increase cGMP enhanced monocyte chemotactic responses. Thus, the initial morphologic response of monocytes to chemoattractants as well as the processes required for sustained directional motility are modulated by cyclic nucleotides.