Mechanisms of Lysosomal Enzyme Release from Human Leukocytes II. EFFECTS OF cAMP AND cGMP, AUTONOMIC AGONISTS, AND AGENTS WHICH AFFECT MICROTUBULE FUNCTION

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Abstract

Selective release of inflammatory materials from leukocyte lysosomes is reduced by compounds which increase cyclic 3′,5′-adenosine monophosphate (cAMP) levels in suspensions of human leukocytes and is augmented by agents which increase cyclic 3′,5′-guanosine monophosphate (cGMP) levels in these cell suspensions. Lysosomal enzymes are released in the absence of phagocytosis when cytochalasin B (5 μg/ml) converts polymorphonuclear leukocytes (PMN) to secretory cells: lysosomes merge directly with the plasma membrane upon encounter of PMN with zymosan, and cells selectively extrude substantial proportions of lysosomal, but not cytoplasmic enzymes. β-Adrenergic stimulation of human leukocytes produced a dose-related reduction in β-glucuronidase release (blocked by 10-6 M propranolol) whereas α-adrenergic stimulation (phenylephrine plus propranolol) was ineffective. In contrast, the cholinergic agonist carbamylcholine chloride enhanced enzyme secretion, an effect blocked by 10-6 M atropine. Incubation of cells with exogenous cAMP or with agents that increase endogenous cAMP levels (prostaglandin E1, histamine, isoproterenol, and cholera enterotoxin) reduced extrusion of lysosomal enzymes; in contrast, exogenous cGMP and carbamylcholine chloride (which increases endogenous cGMP levels), increased β-glucuronidase release. Whereas colchicine (5 × 10-4 M), a drug which impairs microtubule integrity, reduced selective enzyme release, deuterium oxide, which favors microtubule assembly, enhanced selective release of lyosomal enzymes. The data suggest that granule movement and acid hydrolase release from leukocyte lysosomes requires intact microtubules and may be modulated by adrenergic and cholinergic agents which appear to provoke changes in concentrations of cyclic nucleotides.

Authors

Robert B. Zurier, Gerald Weissmann, Sylvia Hoffstein, Sandra Kammerman, Hsin Hsiung Tai