Reduction of lipopolysaccharide-induced interleukin-6 production by the kappa opioid U50,488 in a mouse monocyte-like cell line

Several studies demonstrate that opioids modulate the immune response via opioid receptors expressed directly on the immune cells themselves. Recently, it has been suggested that the kappa opioid system has a modulatory role in various inflammatory diseases including rheumatoid arthritis. This modulation may occur via changes in cytokine secretion by monocyte-derived cells. To further study this opioid–immune relationship, we stimulated P388D1 cells, a mouse monocyte-like cell line, with lipopolysaccharide (LPS) in the presence or absence of the kappa opioid-selective ligand, U50,488. Pretreatment with U50,488 significantly reduced LPS-stimulated interleukin-6 (IL-6) production as measured by ELISA. This effect was mediated by the kappa opioid receptor, because nor-binaltorphimine (nor-BNI), a kappa-selective antagonist, blocked this inhibition. It is likely that this reduction of IL-6 protein by U50,488 treatment is attributed to decreases in IL-6 mRNA. RT-PCR experiments demonstrated that U50,488 treatment significantly reduced the LPS-mediated increase in IL-6 mRNA and that this effect was also blocked by nor-BNI. Understanding the mechanism behind the reduction of proinflammatory cytokine production by opioids may lead to the development of more effective therapeutics for inflammatory diseases.