In vitro and in vivo effects of zinc on cytokine signalling in human T cells.
Aging is associated with changes in the immune response which are collectively called immunosenescence. The changes mainly affect the adaptive immune response and especially the T cell-mediated cellular immune response. There are a few data indicating that the cytokine signalling in T cells is altered with aging. Zinc has been specifically shown to have potent immunomodulatory effects. The aim of the present work was to study the IL-2 and IL-6 cytokine signalling and activation induced cell death (AICD) in T cells of elderly subjects of various ages and from various European countries. These experiments were performed in the frame of European Community financed project called ZINCAGE "Nutritional zinc, oxidative stress and immunosenescence: biochemical, genetic and lifestyle implications for healthy ageing", assembling 17 laboratories from 8 countries through Europe. The study was carried out in a total of 312 French and a group of 201 (26 from Italy, 63 from France, 57 from Greece, 24 from Poland and 30 from Germany) healthy non-institutionalized men and women older than 60 years of age, with available dietary data. Human peripheral blood mononuclear cells (PBMC) were obtained from heparinized blood and were stimulated in vitro by IL-2 or IL-6 for various periods and the phosphorylation of STAT3 and STAT5 was measured by FACScan. The activation induced cell death (AICD) was measured after anti-CD3 and CD28 restimulation for 48h by using the Annexin:FITC Apoptosis Kit. We found that there is an IL-2 signalling defect with aging up to 90 years of age which cannot be modulated by zinc. In contrast at 90 years and over the zinc could reverse the negative signalling effect of IL-2. There is also a signalling defect for STAT3 and STAT5 activation in T cells under IL-6 stimulation with aging and the zinc supplementation could potentiate only the STAT5 activation in the age-group 90 years and over. Studying signalling in PBL from different countries we detected less activation in T cells of subjects from France and the most changes occurred in T cells of subjects from Poland, suggesting no correlation with the plasma zinc status observed in these countries. In vivo zinc supplementation had no effect on IL-2 and IL-6-modulated STAT3 and STAT5 activation. Zinc added in vitro to these T cells even inhibited the stimulation either by IL-2 or by IL-6. Zinc supplementation improved the susceptibility of T cells to AICD in both age-groups, with more efficiency in later ages. Our results suggest that zinc can have a potent immunomodulatory effect via the modulation of cytokine signalling and AICD, however this effect depends on the function and the activation status of the T cells.
Varin
Audrey
A
Department of Virology, EA 3186 IFR 133, Franche-Comte University, Hôpital Saint-Jacques, Besançon cedex, France.
Larbi
Anis
A
Dedoussis
George V
GV
Kanoni
Stavroula
S
Jajte
Jolanta
J
Rink
Lothar
L
Monti
Daniela
D
Malavolta
Marco
M
Marcellini
Fiorella
F
Mocchegiani
Eugenio
E
Herbein
Georges
G
Fulop
Tamas
T
D000368:Aged; D000369:Aged, 80 and over; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*; D014131:Trace Elements / Q000008:administration & dosage / Q000494:pharmacology*; D015032:Zinc / Q000008:administration & dosage / Q000494:pharmacology*
D007376:Interleukin-2; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D014131:Trace Elements; D015032:Zinc