Melatonin-Induced Hematopoietic-Neuroendocrine Cytokines

We have reported that melatonin may rescue bone marrow cells from apoptosis induced either in vivo or in vitro by cancer chemotherapy compounds. The number of granulocyte-macrophage colony-forming units cultured with suboptimal concentrations of colony stimulating factor was higher in presence of melatonin both at physiological and pharmacological concentration. CD4+,Thy-1.2+cells depletion or addition of anti mouse interleukin-4 (IL-4) monoclonal antibodies prevented both effects of melatonin. We proposed that melatonin represents a neuroendocrine regulator of IL-4 production in bone marrow T-helper cells and that IL-4 stimulates adherent stromal cells to produce granulocyte/macrophage colony-stimulating factor. However, in further investigations we did not find any direct evidence of the ability of melatonin to stimulate IL4. We found that beside anti-IL4 antibodies also the specific opioid antagonist naltrexone neutralized the colony stimulating activity of melatonin. SDS-PAGE and blotting analysis of gel filtration fractions of supernatants from bone marrow cells cultures revealed that upon melatonin stimulation, T-helper cells release a 15 and 67 kDa opioid peptides which are recognized both by anti-common opioid sequence and anti-IL4 monoclonal antibodies. The term “neuroendocrine cytokines” seems thus to fit the properties of these IL4-like and opioid-like melatonin-induced peptides which might represent a new family of immunological and hematopoietic regulators.