INHIBITION OF INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA SYNTHESISFOLLOWING TREATMENT OF MACROPHAGES WITH THE KAPPA-OPIOID AGONIST U50,488H

Previous reports from this laboratory, and others, have shown that exo genous mu and kappa opioids modulate both cellular and humoral immune responses. Our earlier work has suggested that accessory cells may ser ve as a target for the direct effects of kappa opioid compounds. In th e present study, the function of the macrophage cell line P388D1 was m odulated by the kappa-selective opioid agonist U50,488H {trans-3,4-dic hloro-N-methyl-N-[7-(1- pyrrolidinyl)cyclohexyl]benzene-acetamide meth anesulfonate}. Lipopolysaccharide-induced interleukin (IL)-1 and tumor necrosis factor-alpha production were inhibited after the administrat ion of nanomolar concentrations of U50,488H. Furthermore, inhibition o f IL-1 produced by the P388D1 cell line was reversed by both the class ical opioid antagonist naloxone and by the kappa opioid receptor antag onist norbinaltorphimine. Examination of IL-1 mRNA levels in P388D1 by northern blot analysis showed that the inhibition mediated by U50,488 H apparently occurred at the level of transcription. On the other hand , U50,488H failed to modulate the production of IL-6 by this macrophag e-like cell line. In addition, U50,488H failed to modulate the product ion of either IL-1 or tumor necrosis factor-alpha from the macrophage- like cell line RAW 264.7, an indication that subpopulations of macroph ages 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 i n the production of cytokines.