Zinc signals promote IL-2-dependent proliferation of T cells.
Zinc signals, i.e. a change of the intracellular concentration of free zinc ions in response to receptor stimulation, are involved in signal transduction in several immune cells. Here, the role of zinc signals in T-cell activation by IL-2 was investigated in the murine cytotoxic T-cell line CTLL-2 and in primary human T cells. Measurements with the fluorescent dyes FluoZin-3 and Zinquin showed that zinc is released from lysosomes into the cytosol in response to stimulation of the IL-2-receptor. Activation of the ERK-pathway was blocked by chelation of free zinc with N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, whereas zinc was not required for STAT5 phosphorylation. In addition, the key signaling molecules MEK and ERK were activated in response to elevated free intracellular zinc, induced by incubation with zinc and the ionophore pyrithione. Downstream of ERK activation, ERK-specific gene expression of c-fos and IL-2-induced proliferation was found to depend on zinc. Further experiments indicated that inhibition of MEK and ERK-dephosphorylating protein phosphatases is the molecular mechanism for the influence of zinc on this pathway. In conclusion, an increase of cytoplasmic free zinc is required for IL-2-induced ERK signaling and proliferation of T cells.
Kaltenberg
Jennifer
J
Institute of Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Plum
Laura M
LM
Ober-Blöbaum
Julia L
JL
Hönscheid
Andrea
A
Rink
Lothar
L
Haase
Hajo
H
D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005456:Fluorescent Dyes / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D017136:Ion Transport / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D011083:Polycyclic Compounds / Q000032:analysis; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects*; D013871:Thiones / Q000494:pharmacology; D014105:Tosyl Compounds / Q000032:analysis; D015032:Zinc / Q000494:pharmacology / Q000502:physiology*
D002614:Chelating Agents; C451182:FluoZin-3; D005456:Fluorescent Dyes; D007376:Interleukin-2; D007476:Ionophores; D011083:Polycyclic Compounds; D011725:Pyridines; D015363:Quinolones; D015375:Receptors, Interleukin-2; D013871:Thiones; D014105:Tosyl Compounds; C008704:pyrithione; D048049:Extracellular Signal-Regulated MAP Kinases; D010749:Phosphoprotein Phosphatases; D015032:Zinc; C084731:zinquin