Inhibition of interleukin-1 and tumor necrosis factor-alpha synthesis following treatment of macrophages with the kappa opioid agonist U50, 488H

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 273; no. 3; pp. 1491 - 1496
• Main Authors: Belkowski, S M, Alicea, C, Eisenstein, T K, Adler, M W, Rogers, T J
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.1995
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics - pharmacology; Animals; Blotting, Northern; Cell Line; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - biosynthesis; Interleukin-1 - genetics; Interleukin-6 - biosynthesis; Macrophages - drug effects; Macrophages - metabolism; Mice; Naloxone - pharmacology; Pyrrolidines - pharmacology; Receptors, Opioid, kappa - agonists; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0022-3565; 1521-0103

Previous reports from this laboratory, and others, have shown that exogenous mu and kappa opioids modulate both cellular and humoral immune responses. Our earlier work has suggested that accessory cells may serve as a target for the direct effects of kappa opioid compounds. In the present study, the function of the macrophage cell line P388D1 was modulated by the kappa-selective opioid agoinst U50,488H (trans-3,4-dichloro-N-methyl-N-[7-(1- pyrrolidinyl)cyclohexyl]benzene-acetamide methanesulfonate). Lipopolysaccharide-induced interleukin (IL)-1 and tumor necrosis factor-alpha production were inhibited after the administration of nanomolar concentrations of U50,488H. Furthermore, inhibition of IL-1 produced by the P388D1 cell line was reversed by both the classical opioid antagonist naloxone and by the kappa opioid receptor antagonist norbinaltorphimine. Examination of IL-1 mRNA levels in P388D1 by northern blot analysis showed that the inhibition mediated by U50, 488H apparently occurred at the level of transcription. On the other hand, U50,488H failed to modulate the production of IL-6 by this macrophage-like cell line. In addition, U50,488H failed to modulate the production of either IL-1 or tumor necrosis factor-alpha from the macrophage-like cell line RAW 264.7, an indication that subpopulations of macrophages exist with different sensitivities to opioids. These results are consistent with a growing body of data which suggests that a component of the inhibition mediated by opioid compounds involves a reduction in the production of cytokines.