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 apoptosis induced either in vivo or in vitro by cancer chemotherapy compounds via bone marrow T-cells and endogenous release of granulocyte-macrophage colony-stimulating factor. Here we show that the number of granulocyte/macrophage colony-forming units cultured with suboptimal concentrations of colony-stimulating factor was higher in the presence of melatonin 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 incubation with etoposide, the concentration of myeloid precursors was 43 +/- 8 per 10(5) cells. The melatonin+etoposide value was 68 +/- 7, whereas that of melatonin+etoposide+anti-interleukin 4 was 38 +/- 6. Melatonin was also ineffective when bone marrow cells were separated in adherent and nonadherent populations. Supernatants from nonadherent cells incubated with melatonin proved to contain interleukin 4 activity which, however, showed its influence on unseparated bone marrow and adherent cells but not on nonadherent cells. It is proposed that melatonin represents a neuroendocrine regulator of interleukin 4 production in bone marrow T-helper cells. Interleukin 4 may then stimulate adherent stromal cells to produce granulocyte/macrophage colony-stimulating factor. Such a neuroendocrine-cytokine mechanism may explain the hematopoietic rescue of melatonin as well as its antitumoral and immunoenhancing properties.
Maestroni
G J
GJ
Center for Experimental Pathology, Istituto cantonale di Patologia, Locarno, Switzerland.
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Lissoni
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D017077:Culture Media, Conditioned; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D008550:Melatonin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D015847:Interleukin-4; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008550:Melatonin