Metallothioneins/PARP-1/IL-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply.
Metallothioneins (MTs) play pivotal role in zinc-related cell homeostasis because of their high affinity for this trace element which is in turn relevant against oxidative stress and for the efficiency of the entire immune system, including natural killer (NK) cell activity. In order to accomplish this role, MTs sequester and/or dispense zinc during stress and inflammation to protect cells against reactive oxygen species. MTs gene expression is affected by IL-6 for a prompt immune response. Concomitantly, MTs release zinc for the activity of antioxidant zinc-dependent enzymes, including poly(ADP-ribose)polymerase-1(PARP-1), which is involved in base excision DNA-repair. This role of MTs is peculiar in young adult-age during transient stress and inflammation, but not in ageing because stress-like condition and inflammation are persistent. This may lead MTs to turn-off from role of protection in young age to deleterious one in ageing with subsequent appearance of age-related diseases (severe infections). The aim is to study the role played by MTs/IL-6/PARP-1 interplay on NK cell activity in elderly, in old infected patients (acute and remission phases by bronchopneumonia infection) and in health nonagenarian/centenarian subjects. MTmRNA is high in lymphocytes from elderly people coupled with high IL-6, low zinc ion bioavailability, decreased NK cell activity and impaired capacity of PARP-1 in base excision DNA-repair. The same trend in this altered physiological cascade during ageing also occurs in old infected patients (both acute and remission phases) with more marked immune damage, inflammatory condition and very impaired PARP-1 in base excision DNA-repair. By contrast, centenarian subjects display low MTmRNA, good zinc ion bioavailability, satisfactory NK cell activity and higher capacity of PARP-1 in base excision DNA-repair. These findings clearly demonstrate that the sequester of zinc by MTs in ageing is deleterious because leading to low zinc ion bioavailability with subsequent impairment of PARP-1 and NK cell activity and appearance of severe infections. Physiological zinc supply (12 mg Zn(++)/day) for 1 month in elderly and in old infected patients (remission phase) restores NK cells activity with values observed in health centenarians. Therefore, the zinc ion bioavailability by zinc-bound MTs homeostasis is pivotal to reach health longevity and successful ageing.
Mocchegiani
Eugenio
E
Immunology Center (Section Nutrition, Immunity and Ageing), Research Department Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121, Ancona, Italy. e.mocchegiani@inrca.it
Muzzioli
Mario
M
Giacconi
Robertina
R
Cipriano
Catia
C
Gasparini
Nazzarena
N
Franceschi
Claudio
C
Gaetti
Remo
R
Cavalieri
Elisabetta
E
Suzuki
Hisanori
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007239:Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D015032:Zinc / Q000008:administration & dosage / Q000097:blood*
D015850:Interleukin-6; D012333:RNA, Messenger; D008668:Metallothionein; D011065:Poly(ADP-ribose) Polymerases; D015032:Zinc