Methionine-enkephalin stimulates interleukin-6 mRNA expression: Human plasma levels in coronary artery bypass grafting

Opioid peptides have the ability to regulate immunocompetent cells. The present study extends this phenomenon to include an interaction with interleukin (IL)-6. We demonstrate that methionine-enkephalin (met- enkephalin) stimulates IL-6 mRNA expression in mice as determined by RNA isolation and hybridization with IL-6 cDNA. In mice, met-enkephalin [0.1 and 1 mg/kg intraperitoneal exposure for 6 days] also enhanced serum IL-6 levels. The in vivo data demonstrate that met-enkephalin upregulates IL-6 levels via an increase in transcriptional activity. Further, pre- and postoperative IL- 6 and met-enkephalin levels were determined in the plasma of seven patients. First an increase in met-enkephalin plasma levels occurred (8.9±2.9 to 135±18 pg/ml; P<0.005), and then an increase in plasma IL-6 levels (2.1±1.5 to 237±50 pg/ml; P<0.001), suggesting that, as in mice, met-enkephalin induces IL-6 production. Taken together, the data strongly suggest that opioid peptides may be important as one of the chemical signaling molecules initiating the diffuse inflammatory response associated with coronary artery bypass grafting.