Untersuchung von Zinksignalen während Aktivierung und Reifung in Monozyten

Zinc is an essential trace element for the immune system and regulates the function of monocytes. Intracellular free zinc can bind reversibly to regulatory sites in signaling proteins, whereby changes of free zinc influence signal transduction. To achieve a broad picture about the role of zinc in monocytes, short- and long-term changes in intracellular free zinc were investigated. Experiments with the myeloid cell line HL-60 showed that short-term zinc signals after stimulation with lipopolysaccharide (LPS) were characteristic for differentiated, tumor necrosis factor-alpha secreting cells, and were essential for LPS-induced signal transduction. LPS-induced zinc signals were repetitive and derived from intracellular stores in Raw 264.7 cells. This was partially mediated by tyrosine kinases, as demonstrated by a screening with 16 inhibitors for signal transduction components. Additionally, inhibitory G proteins could be involved in the generation of the LPS-induced zinc signal. Furthermore the observed transient increase in intracellular free zinc after activation of inhibitory G proteins alone suggests an impact of zinc in the signaling of G protein coupled receptors. Myelopoiesis is augmented during zinc deficiency in mice, indicating an inhibitory function of zinc. In this work, a long-term decrease of intracellular free zinc was observed during differentiation of HL-60 towards monocytes with 1alpha,25-dihydroxyvitamin D3 (1,25VD3). This was accompanied by a decrease of zinc importer expression and an upregulation of the zinc binding proteins S100A8 and -A9. The use of the zinc chelator TPEN enhanced 1,25VD3-induced expression of monocytic surface markers (CD14/CD11b) in three cell lines and enhanced functionality of HL-60 (oxidative burst, TNF secretion). Thus, not only short-term signals, but also long-term changes of zinc homeostasis serve as endogenous modulators of monocyte function. Zinc inhibits the cAMP synthesizing enzyme adenylate cyclase (AC) thereby lowering cAMP concentrations after stimulation with forskolin in HL-60. Conversely, TPEN increased cAMP synthesis indicating that AC is partially inhibited already by physiological levels of free zinc in HL-60. Because cAMP is synthesized during 1,25VD3-induced differentiation and enhances this process, the observed decrease of intracellular free zinc after treatment with 1,25VD3 could acts as a physiological mechanism to facilitate differentiation towards monocytes. Thereby, this work discovers a thus far unknown function of zinc in the immune system and expands the understanding of myeloid differentiation. This knowledge could be used to modulate monocytic differentiation and lead to new approaches for the therapy of acute myeloid leukemia.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2010

Author dc:creator

• Dubben, Svenja Daniela

Contributors dc:contributor

• Rink, Lothar

• info:eu-repo/classification/ddc/570
• Monozyt
• Zink
• Zelldifferenzierung
• Immunsystem
• Adenylatcyclase
• Homöostase
• Biowissenschaften, Biologie
• Zinktransporter
• Vitamin D
• 1alpha,25-Dihydroxyvitamin D3
• zinc
• monocytes
• adenylatecyclase
• differentiation

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-114064%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51812