REGULATION OF 5-LIPOXYGENASE ACTIVITY IN MONONUCLEAR PHAGOCYTES - CHARACTERIZATION OF AN ENDOGENOUS CYTOSOLIC INHIBITOR

The proinflammatory leukotrienes (LT) play important roles in host def ense and disease states. However, no endogenous mechanisms to downregu late 5-lipoxygenase (5-LO), the enzyme catalyzing LT synthesis, have b een described. We observed that the cytosolic fraction of rat alveolar macrophages (AMs) and peritoneal macrophages (PMs), and of peripheral blood monocytes (PBMs) contain substantial amounts of 5-LO protein, b ut little detectable 5-LO activity. We therefore examined these mononu clear phagocyte (MNP) cytosolic fractions for inhibitory activity agai nst 5-LO. MNP cytosol dose-dependently reduced the 5-LO activity in ne utrophil (PMN) cytosol and AM membrane. Furthermore, MNP cytosol dose- dependently prolonged the lag phase of soybean lipoxygenase (LO) witho ut affecting the rate of product formation. This effect was overcome b y subsequent addition of 13(S)-hydroperoxy-9-cis-11-trans-octadecadien oic (13-HpOD), suggesting that the active factor scavenges hydroperoxi des. Inactivation by boiling and proteinase K suggest that is a protei n. We speculate that this cytosolic factor(s) may serve as an endogeno us means for the down-regulation of 5-LO in macrophages.