Metallothionein (I+II) confers, via c-myc, immune plasticity in oldest mice: model of partial hepatectomy/liver regeneration

Abstract

Because of its similarity to ageing in impaired immune efficiency 48 h after surgical procedures on young partially hepatectomised mice, partial hepatectomy/liver regeneration (pHx) provides a good model for the study of inflammation in ageing. In old age, high metallothionein (I+II) (MT) sequesters a substantial number of intracellular zinc ions consequently leading to low zinc ion bioavailability for an adequate immune response. Corticosterone and IL-6 affect MTmRNA induction in inflammation and after pHx against oxidative damage. The aim of this study was to investigate the role played by MT in conferring immune plasticity in ageing and in very old age using the pHx model. 48 h after their partial hepatectomy, the crude zinc balance was negative in young, old and very old mice coupled with increased MT, corticosterone, sIL-6R and IL-6. Concomitantly, Natural Killer (NK) cell activity and IL-2 production decreased. Complete restoration of the nutritional-endocrine-immune parameters occurred 15 days from the surgical procedures in young and very old mice, but not in old or transgenic mice overexpressing MT. A significant positive or inverse correlation among nutritional-endocrine-immune parameters exists in young and very old mice, but not in old mice during liver regeneration. Since MT also affects c-myc, the gene expression of c-myc declines from 48 h to days 7 and 15 after pHx in young and very old mice, but remains constantly high in old pHx mice for the same days. This circumstance leads to the appearance of tumours in the long run in old pHx mice and survival times that are shorter than old sham controls. Because complete remodelling also occurs in IL-6 and in sIL-6R in very old mice during liver regeneration, the pre-existing inflammation is not detrimental in very old age. As such, very old mice are still responsive to large inflammation, such as pHx, thanks to correct MT homeostasis. Correct MT homeostasis, via c-myc, is therefore pivotal in both suitable liver regeneration and in conferring immune plasticity with subsequent successful ageing. High MT plays an extremely harmful role in ageing: on one hand it lowers zinc ion bioavailability levels required for immune efficiency and on the other hand it increases c-myc expression. The combination of immune depression and enhanced c-myc, via high MT, may trigger the appearance of age-related degenerative diseases.

Hepatic Expression of Metallothionein I/II, Glycoprotein 96, IL-6, and TGF-βin Rat Strains with Different Susceptibilities to Experimental Autoimmune Encephalomyelitis

“…Moreover, owing to their ability to control Zn-dependent transcription factors, protein synthesis, cellular energy, levels and metabolism, they are also critically involved in cell growth and multiplication [37, 52], as well as in the maintenance of neuroimmune homeostasis and processes of apoptosis [51]. Accordingly, we can speculate that high constitutive MT expression in AO rats and high inducible hepatic MTs in DA rats contributed to lower susceptibility to EAE and to the restrain of autoimmune and inflammatory response.…”

Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing?

“…Moreover, very old mice display still efficient thymic functions during liver regeneration after partial hepatectomy (model of acute and constant inflammation) [34]. In addition, the presence of involuted thymus in stressed MT transgenic mice [22] further supports the involvement of high MT in thymic involution during ageing.…”

Zinc, Immune Plasticity, Aging, and Successful Aging: Role of Metallothionein

“…As a consequence, very old individuals become “high responders” to oxidative stress, as occurring in the young 1. Indeed, the lack of response to a great inflammation (such as partial hepatectomy) in old age provokes a shorter survival in old pHx mice in comparison with old sham controls 14. Indeed, old pHx mice display a greater incidence of cancer and infections 14.…”

“…Indeed, the lack of response to a great inflammation (such as partial hepatectomy) in old age provokes a shorter survival in old pHx mice in comparison with old sham controls 14. Indeed, old pHx mice display a greater incidence of cancer and infections 14. Thus, a good functioning of liver immune plasticity is pivotal to reach successful aging.…”

“…A peculiar role of MT is played during partial hepatectomy/liver regeneration, with a strong MT induction that is useful, other than in facilitating the liver regeneration by various hepatocyte growth factors, in protecting the cells by the inflammation after partial hepatectomy. It has been shown that high MT, either as gene expression or protein, is present in young pHx mice at 48 h from pHx coupled with low zinc ion bioavailability, high IL‐6, and impaired thymic and extrathymic T cell pathways 9,14. A complete downregulation of MT and IL‐6 followed by a restoration of the immune efficiency occurs in the late period of the compensatory liver growth (7th and 15th day from pHx) 14.…”