Decreased leukotriene C-4 synthesis accompanies adherence-dependent nuclear import of 5-lipoxygenase in human blood eosinophils

The enzyme 5-lipoxygenase (5-LO) catalyzes the synthesis of leukotrienes (L Ts) from arachidonic acid (AA). Adherence or recruitment of polymorphonucle ar neutrophils (PMN) induces nuclear import of 5-LO from the cytosol, which is associated with enhanced LTB4 synthesis upon subsequent cell stimulatio n. In this study, we asked whether adherence of human eosinophils (EOS) cau ses a similar redistribution of 5-LO and an increase in LTC4 synthesis. Pur ified blood EOS examined either in suspension or after adherence to fibrone ctin for 5 min contained only cytosolic 5-LO, Cell stimulation resulted in activation of 5-LO, as evidenced by its translocation to membranes and LTC, synthesis. As with PMN, adherence of EOS to fibronectin for 120 min caused nuclear import of 5-LO. Unexpectedly, however, adherence also caused a tim e-dependent decrease in LTC4 synthesis: EOS adhered for 120 min produced 90 % less LTC4 than did cells adhered for 5 min. Adherence did not diminish th e release of [H-3]AA from prelabeled EOS or reduce the synthesis of the pro stanoids thromboxane and PGE,. Also, inhibition of LTC4 production caused b y adherence could not be overcome by the addition of exogenous AA, Adherenc e increased, rather than decreased, LTC4 synthase activity. However, the st imulation of adherent EOS failed to induce translocation of 5-LO from the n ucleoplasm to the nuclear envelope, This resistance to activation of the nu clear pool of 5-LO with diminished LT production represents a novel mode of regulation of the enzyme, distinct from the paradigm of up-regulated LT sy nthesis associated with intranuclear localization of 5-LO observed in PMN a nd other cell types.