Dynorphin-A(1-17) decreases nitric oxide release and cytotoxicity induced with lipopolysaccharide plus interferon-γ in murine macrophage cell line J774

Nitric oxide (NO) is an important mediator of cytotoxicity caused by macrophages or by their resident counterpart in brain-glial cells. Modulation of NO release by both activated macrophages and glial cells has been reported in the presence of endogenous (peptide) and synthetic (non-peptide) agonists with kappa opioid-receptors (KOR) selectivity. The data obtained with macrophages and glial cells are contradictory: enhanced NO release by mouse macrophages was reported in the presence of synthetic agonist of KOR selectivity (Neuropeptides 32 (1998) 287), and decreased NO release by glial cells, in the presence of dynorphin-A((1-8)), endogenous opioid peptide with KOR selectivity (J. Biomed. Sci. 7 (2000) 241). In this study, we used a murine cell line J774 of macrophage origin and examined the effect of dynorphin-A((1-17)), endogenous opioid peptide with selectivity for KOR, on NO release induced with lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). Dynorphin-A((1-17)) was chosen since in comparison to dynorphin-A((1-13)), it is more resistant to biodegradation (Peptides 17 (1996) 983). and its effects during prolonged treatment of cells could be more pronounced. The effect of dynorphin-A((1-17)) on NO release was compared to its effect on cytotoxicity, induced with LPS plus IFN-gamma. The data obtained have shown that activation-induced NO release by J774 cells is decreased in the presence of dynorphin-A((1-17)). This was associated with deceased LPS and IFN-gamma-induced cytotoxicity of J774 cells, suggesting their causal relationship. Neither of the observed effects of dynorphin-A could be prevented with the KOR selective antagonist, norbinaltorphimine, suggesting that they are mediated via non-opioid mechanism. By diminishing NO release dynorphin-A((1-17)) may affect cytotoxic ability of macrophages, but may also beneficially influence inflammation-induced damage of local tissue. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.