The variations during the circadian cycle of liver CD1d-unrestricted NK1.1+TCRγ/δ+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice

Eugenio Mocchegiani, Robertina Giacconi, Catia Cipriano, Nazzarena Gasparini, Gianni Bernardini, Marco Malavolta, Marta Menegazzi, Elisabetta Cavalieri, Mario Muzzioli, Anna Rosa Ciampa, Hisanori Suzuki

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

NKT cells derive from the thymus and home to the liver. Liver NKT cells can be divided in two groups: 'classical' and 'non-classical'. The first is CD1d-restricted, the second is CD1d-unrestriced. NKT cells (classical and non-classical) co-express T-cell receptor (TCR) and NK-cell marker (NK1.1), display cytotoxicity and produce IFN-γ under IL-12 stimulation affecting, thereby, Th1 response and innate immunity. NK1.1+TCRα/ β+ cells belong to both groups. NK1.1+TCRγ/ δ+ cells belong to the second group. Anyway, both NKT cell subtypes, via IFN-γ production, protect against viruses and bacteria from early in life. Immune variations as well as zinc rhythmicity during the circadian cycle confer the immune plasticity, which is essential for successful ageing. Liver NK1.1+TCRγ/δ+ cells, rather than TCRα/β+, from young and very old mice display 'in vitro' (under IL-12 stimulation) nocturnal peaks in cytotoxicity and IFN-γ production. The acrophase of liver NK1. 1+TCRγ/δ+ cells is present in young and very old mice, not in old. The interplay among zinc-bound metallothionein (MT)/IL-6/gp130/poly(ADP-ribose) polymerase-1 (PARP-1) may be involved in conferring plasticity to liver NK1.1+TCRγ/δ+ cells. IL-6, via sub-unit receptor gp130, induces MTmRNA. At night, gene expressions of MT, IL-6, gp130 are lower in very old mice than old and young MT-I transgenic mice (MT-I*). In very old mice, this phenomenon allows limited sequester of intracellular zinc from MT leading to good free zinc ion bioavailability for immune efficiency and zinc-dependent PARP-1 activity. Indeed (1) in vitro, high IL-6 provokes strong accumulation of MT, impaired cytotoxicity and low zinc ion bioavailability in liver NK1.1 +TCRγ/δ+ cells exclusively from old and MT-I* mice. (2) The ratio total/endogen PARP-1 activity is higher in very old than in old and MT-I* mice, suggesting a higher capacity of PARP-1 in base excision DNA-repair in very old age thanks to low zinc-bound MT. Cytotoxicity and IFN-γ production from liver NK1.1 +TCRγ/δ+ cells are thus preserved leading to successful ageing. In conclusion, MT/IL-6/gp130/PARP-1 interplay may confer plasticity to liver CD1d-unrestricted NK1.1+TCRγ/ δ+ cells, where MT, IL-6, gp130 are the main upstream protagonists, and PARP-1 is the main downstream protagonist in immunosenescence.

Original languageEnglish
Pages (from-to)775-788
Number of pages14
JournalExperimental Gerontology
Volume39
Issue number5
DOIs
Publication statusPublished - May 2004

Fingerprint

Poly(ADP-ribose) Polymerases
Metallothionein
T-Cell Antigen Receptor
Liver
Interleukin-6
Aging of materials
Zinc
Natural Killer T-Cells
Cytotoxicity
Plasticity
Interleukin-12
DNA Repair
Biological Availability
Poly (ADP-Ribose) Polymerase-1
Ions
Thymus
Periodicity
Viruses
Innate Immunity
Gene expression

Keywords

  • gp130
  • IFN-γ
  • IL-12
  • IL-6
  • Liver NKT cells
  • Metallothionein
  • Poly(ADP-ribose) polymerase-1
  • Successful ageing
  • T-cell receptors

ASJC Scopus subject areas

  • Ageing
  • Medicine(all)

Cite this

The variations during the circadian cycle of liver CD1d-unrestricted NK1.1+TCRγ/δ+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice. / Mocchegiani, Eugenio; Giacconi, Robertina; Cipriano, Catia; Gasparini, Nazzarena; Bernardini, Gianni; Malavolta, Marco; Menegazzi, Marta; Cavalieri, Elisabetta; Muzzioli, Mario; Ciampa, Anna Rosa; Suzuki, Hisanori.

In: Experimental Gerontology, Vol. 39, No. 5, 05.2004, p. 775-788.

Research output: Contribution to journalArticle

Mocchegiani, Eugenio ; Giacconi, Robertina ; Cipriano, Catia ; Gasparini, Nazzarena ; Bernardini, Gianni ; Malavolta, Marco ; Menegazzi, Marta ; Cavalieri, Elisabetta ; Muzzioli, Mario ; Ciampa, Anna Rosa ; Suzuki, Hisanori. / The variations during the circadian cycle of liver CD1d-unrestricted NK1.1+TCRγ/δ+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice. In: Experimental Gerontology. 2004 ; Vol. 39, No. 5. pp. 775-788.
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T1 - The variations during the circadian cycle of liver CD1d-unrestricted NK1.1+TCRγ/δ+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice

AU - Mocchegiani, Eugenio

AU - Giacconi, Robertina

AU - Cipriano, Catia

AU - Gasparini, Nazzarena

AU - Bernardini, Gianni

AU - Malavolta, Marco

AU - Menegazzi, Marta

AU - Cavalieri, Elisabetta

AU - Muzzioli, Mario

AU - Ciampa, Anna Rosa

AU - Suzuki, Hisanori

PY - 2004/5

Y1 - 2004/5

N2 - NKT cells derive from the thymus and home to the liver. Liver NKT cells can be divided in two groups: 'classical' and 'non-classical'. The first is CD1d-restricted, the second is CD1d-unrestriced. NKT cells (classical and non-classical) co-express T-cell receptor (TCR) and NK-cell marker (NK1.1), display cytotoxicity and produce IFN-γ under IL-12 stimulation affecting, thereby, Th1 response and innate immunity. NK1.1+TCRα/ β+ cells belong to both groups. NK1.1+TCRγ/ δ+ cells belong to the second group. Anyway, both NKT cell subtypes, via IFN-γ production, protect against viruses and bacteria from early in life. Immune variations as well as zinc rhythmicity during the circadian cycle confer the immune plasticity, which is essential for successful ageing. Liver NK1.1+TCRγ/δ+ cells, rather than TCRα/β+, from young and very old mice display 'in vitro' (under IL-12 stimulation) nocturnal peaks in cytotoxicity and IFN-γ production. The acrophase of liver NK1. 1+TCRγ/δ+ cells is present in young and very old mice, not in old. The interplay among zinc-bound metallothionein (MT)/IL-6/gp130/poly(ADP-ribose) polymerase-1 (PARP-1) may be involved in conferring plasticity to liver NK1.1+TCRγ/δ+ cells. IL-6, via sub-unit receptor gp130, induces MTmRNA. At night, gene expressions of MT, IL-6, gp130 are lower in very old mice than old and young MT-I transgenic mice (MT-I*). In very old mice, this phenomenon allows limited sequester of intracellular zinc from MT leading to good free zinc ion bioavailability for immune efficiency and zinc-dependent PARP-1 activity. Indeed (1) in vitro, high IL-6 provokes strong accumulation of MT, impaired cytotoxicity and low zinc ion bioavailability in liver NK1.1 +TCRγ/δ+ cells exclusively from old and MT-I* mice. (2) The ratio total/endogen PARP-1 activity is higher in very old than in old and MT-I* mice, suggesting a higher capacity of PARP-1 in base excision DNA-repair in very old age thanks to low zinc-bound MT. Cytotoxicity and IFN-γ production from liver NK1.1 +TCRγ/δ+ cells are thus preserved leading to successful ageing. In conclusion, MT/IL-6/gp130/PARP-1 interplay may confer plasticity to liver CD1d-unrestricted NK1.1+TCRγ/ δ+ cells, where MT, IL-6, gp130 are the main upstream protagonists, and PARP-1 is the main downstream protagonist in immunosenescence.

AB - NKT cells derive from the thymus and home to the liver. Liver NKT cells can be divided in two groups: 'classical' and 'non-classical'. The first is CD1d-restricted, the second is CD1d-unrestriced. NKT cells (classical and non-classical) co-express T-cell receptor (TCR) and NK-cell marker (NK1.1), display cytotoxicity and produce IFN-γ under IL-12 stimulation affecting, thereby, Th1 response and innate immunity. NK1.1+TCRα/ β+ cells belong to both groups. NK1.1+TCRγ/ δ+ cells belong to the second group. Anyway, both NKT cell subtypes, via IFN-γ production, protect against viruses and bacteria from early in life. Immune variations as well as zinc rhythmicity during the circadian cycle confer the immune plasticity, which is essential for successful ageing. Liver NK1.1+TCRγ/δ+ cells, rather than TCRα/β+, from young and very old mice display 'in vitro' (under IL-12 stimulation) nocturnal peaks in cytotoxicity and IFN-γ production. The acrophase of liver NK1. 1+TCRγ/δ+ cells is present in young and very old mice, not in old. The interplay among zinc-bound metallothionein (MT)/IL-6/gp130/poly(ADP-ribose) polymerase-1 (PARP-1) may be involved in conferring plasticity to liver NK1.1+TCRγ/δ+ cells. IL-6, via sub-unit receptor gp130, induces MTmRNA. At night, gene expressions of MT, IL-6, gp130 are lower in very old mice than old and young MT-I transgenic mice (MT-I*). In very old mice, this phenomenon allows limited sequester of intracellular zinc from MT leading to good free zinc ion bioavailability for immune efficiency and zinc-dependent PARP-1 activity. Indeed (1) in vitro, high IL-6 provokes strong accumulation of MT, impaired cytotoxicity and low zinc ion bioavailability in liver NK1.1 +TCRγ/δ+ cells exclusively from old and MT-I* mice. (2) The ratio total/endogen PARP-1 activity is higher in very old than in old and MT-I* mice, suggesting a higher capacity of PARP-1 in base excision DNA-repair in very old age thanks to low zinc-bound MT. Cytotoxicity and IFN-γ production from liver NK1.1 +TCRγ/δ+ cells are thus preserved leading to successful ageing. In conclusion, MT/IL-6/gp130/PARP-1 interplay may confer plasticity to liver CD1d-unrestricted NK1.1+TCRγ/ δ+ cells, where MT, IL-6, gp130 are the main upstream protagonists, and PARP-1 is the main downstream protagonist in immunosenescence.

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KW - IFN-γ

KW - IL-12

KW - IL-6

KW - Liver NKT cells

KW - Metallothionein

KW - Poly(ADP-ribose) polymerase-1

KW - Successful ageing

KW - T-cell receptors

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