title: Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4.
abstract: 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.
authors.affiliation: Center for Experimental Pathology, Istituto cantonale di Patologia, Locarno, Switzerland.
authors.forename: G J
authors.initials: GJ
authors.lastname: Maestroni
authors.forename: A
authors.initials: A
authors.lastname: Conti
authors.forename: P
authors.initials: P
authors.lastname: Lissoni
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D015847:Interleukin-4; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008550:Melatonin