Bidirectional effect of met-enkephalin on macrophage effector functions

Abstract

Met-enkephalin (ME) exerts a bimodal effect on functional activities of rat peritoneal macrophages (PM); in a range of low concentration (10(-9)-10(-7)M) antibody dependent cellular cytotoxicity (ADCC) was markedly stimulated with a simultaneous decrease of Fc gamma receptor (Fc gamma R) medicated phagocytosis while the opposite was observed at 10(-6)-10(-5)M concentrations. Studying the possible underlying mechanism(s) the followings were recorded: (1) ME in all applied concentrations induced an early Na+ influx which was followed by a Ca2+ efflux in the range of low concentrations. In the range of high concentrations Na+ influx was accompanied by a Ca2+ influx. (2) ME at 10(-8) M concentration induced a rise in cGMP level with a plateau in the 60-120th min of incubation. This effect was prevented by 10(-5) M of naloxone. At 10(-6) M concentration a transient rise of cAMP level was recorded which was not affected by naloxone. (3) Verapamil in 10(-6) M abolished both the Ca2+ influx and the rise in cAMP level induced by 10(-6)-10(-5) M ME but not the rise in cGMP level induced by lower ME concentrations. (4) cAMP elevation by high ME concentrations was abolished by enkephalinase inhibitory puromycin. (5) PM-enkephalinase as assessed by the cleavage of fluorogenic substrate L-alanine beta naphthylamide (ABNA), was inhibited by 10(-6)-10(-5) M of ME. This inhibition was abolished by verapamil, but not affected by naloxone. In the range of low concentrations ME appears to act on specific delta opioid receptors and its action is positively coupled to guanylate cyclase. In relatively higher concentrations ME-action is not mediated by specific delta opioid receptors and it appears to involve Ca2+ influx, adenylate cyclase activation as well as the processing of hormone by PM-enkephalinase.

Opioids in Immunologic Processes

“…Most reports have indicated a suppression of phagocytosis with concentrations of met-enkephalin in the nM range (FORIS et al 1986). However, higher concentrations of met -en kephalin (j.lM) were reported to increase phagocytosis (FORIS et al 1984).…”

Characterization of Antibacterial COOH-terminal Proenkephalin-A-derived Peptides (PEAP) in Infectious Fluids

“…In adult thymocytes and T lymphocytes clones, PEA mRNA is not expressed constitutively, but is detected following cell activation. After exogenous administration, enkephalins affect several immunologic functions, including antibody production (12), NK cell activity against tumors and viral infections (13), macrophage and polymorphonuclear leukocyte functions (14,15), graft rejections (16), and mitogenstimulated lymphocyte proliferation (17). Recently, it was shown that very low concentrations of PEA and Met-enkephalin differentially affect IgM and IgG production by B cells (18).…”

Morphine-induced Neuroimmunomodulation in Murine Visceral Leishmaniasis: The Role(s) of Cytokines and Nitric Oxide

“…The dual effects of methionineenkephalin (M-ENK) administration in rats, where 1 mg/kg dose decreased and the lower doses (0.1-100 μg/kg) enhanced the immune responses, also indicate interaction with multiple opioid receptors (Foris et al 1986). The augmentation of immune parameters such as phagocytosis, cytotoxicity and production of various cytokines, and NO, within a few minutes of morphine administration, and their decrease after 24 h indicate the time-dependence of the biphasic effects of morphine (Pacifici et al 1994(Pacifici et al , 1995(Pacifici et al , 2000.…”