Granulopoietic growth factors. Cytokine and cellular regulation of GM-CSF and G-CSF production

Detta är en avhandling från Department of Hematology, University Hospital, S-221 85 Lund, Sweden

Sammanfattning: Granulocyte-macrophage- (GM-) and granulocyte- (G-) colony stimulating factor (CSF) are important cytokines in the regulation of hematopoiesis and for the function of mature blood cells. They are also involved in the cytokine network regulating the inflammatory and immune response. The aim of this study was to investigate the regulation of GM- and G-CSF production at the cellular level. The studies focused on the secretion by monocytes derived from peripheral blood of healthy subjects and by endothelial cells derived from human umbilical cord veins. The cells were cultured in vitro and the production of GM-CSF and G-CSF measured by immunoassays or RT-PCR. The results show that GM-CSF and G-CSF secretion can be separately modulated within the same cell system, and furthermore that there are differences in the regulation of GM- and G-CSF secretion between the different cell types. G/GM-CSF secretion by endothelial cells is regulated by the presence or absence of a stimulus in a "switch-on - switch-off" manner, with interleukin (IL-) 1 being the most effective stimulus. No factors down-regulate G/GM-CSF secretion by endothelial cells. However, corticosteroids and the addition of neutrophils enhance G-CSF secretion by activated endothelial cells. Secretion by monocytes is induced by endotoxin and IL-1. Activated monocytes continue to secrete G/GM-CSF also when stimulus is removed. However, the secretion eventually ceases due to the effect of down-regulatory factors. Monocytes inhibit by the secretion of IL-10 in an autocrine manner GM-CSF secretion but not G-CSF secretion. The addition of T-lymphocytes increases the production of monocyte-derived IL-10. Furthermore, corticosteroids selectively down-regulate GM-CSF but not G-CSF secretion by monocytes. IL-4 and IL-13 down-regulate GM-CSF and G-CSF secretion by monocytes to the same extent. Neutrophils and mononocytes modulate the biological activity of secreted GM- and G-CSF by absorption of the cytokines. The interpretation of the results is that G/GM-CSF secreted by monocytes function in the local compartment, and the production is therefore regulated in a more complex manner. Endothelial cells are by their production of especially G-CSF responsible for the long-range activity.

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