COLONY-STIMULATING ACTIVITY AND HEMATOPOIETIC RESCUE FROM CANCER-CHEMOTHERAPY COMPOUNDS ARE INDUCED BY MELATONIN VIA ENDOGENOUS INTERLEUKIN-4

We have reported that melatonin may rescue bone marrow cells from apop tosis induced either in vivo or in vitro by cancer chemotherapy compou nds via bone marrow T-cells and endogenous release of granulocyte-macr ophage colony-stimulating factor. Here me show that the number of gran ulocyte/macrophage colony-forming units cultured with suboptimal conce ntrations of colony-stimulating factor was higher in the presence of m elatonin both at physiological and pharmacological concentrations. CD4 (+),Thy-1.2(+) cell depletion or addition of anti-mouse interleukin 4 monoclonal antibodies prevented both effects of melatonin. Upon incuba tion with etoposide, the concentration of myeloid precursors was 43 +/ - 8 per 10(5) cells. The melatonin+etoposide value was 68 +/- 7, where as that of melatonin+etoposide+anti-interleukin 4 was 38 +/- 6. Melato nin was also ineffective when bone marrow cells were separated in adhe rent and nonadherent populations. Supernatants from nonadherent cells incubated with melatonin proved to contain interleukin 4 activity whic h, however, showed its influence on unseparated bone marrow and adhere nt cells but not on nonadherent cells. It is proposed that melatonin r epresents a neuroendocrine regulator of interleukin 4 production in bo ne marrow T-helper cells. Interleukin 4 may then stimulate adherent st romal cells to produce granulocyte/macrophage colony-stimulating facto r. Such a neuroendocrine-cytokine mechanism may explain the hematopoie tic rescue of melatonin as well as its antitumoral and immunoenhancing properties.