The effect of melatonin on cellular activation processes in human blood

The pineal hormone melatonin, due to its lipophilic nature, has access to every cell and every part of a cell in the body, suggesting that it could exert effects on blood immune cells. The regulation of the activation of monocytes may be important in a number of diseases, especially pathophysiological conditions associated with inflammatory reactions. Considering this, a study on the effect of melatonin on monocytes in whole blood was carried out. Melatonin added at a final concentration of 5 ng/mL to whole blood in vitro reduced lipopolysaccharide (LPS)-induced tissue factor (TF) activity in monocytes by 55% in blood from a group of subjects with melatonin-sensitive cells. At even lower concentrations of melatonin (20-50 pg/mL) and in the physiological range, a trend of suppressed LPS-induced TF activity by approximately 20% was seen. A further indication of a downregulation of LPS-stimulated monocytes by melatonin was shown by its reduction of LPS-induced tumor necrosis factor (TNF). Twenty to one hundred pg/mL melatonin caused a significant reduction of LPS-induced TNF production by approximately 25-30%. In contrast, melatonin at a final concentration of 10 pg/mL, added to whole blood incubated with LPS and also the phorbol ester, PMA, caused a significant rise of 25%; whereas 100 pg/mL enhanced LPS + PMA-induced TNF by approximately 80% as compared to LPS + PMA alone. These effects were not detectable during the winter darkness of Tromsø (70 degrees N), probably due to the high content of melatonin in the blood even at daytime. These results show that melatonin may have a beneficial effect by suppressing the expression of TF activity in LPS-stimulated monocytes. Furthermore, the results indicate that LPS-induced TF in monocytes of whole blood is independent of protein kinase C (PKC) activation. Melatonin is probably amplifying cellular activation reactions that are PKC-dependent. This may be physiologically important in upregulation of the immune system.