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

Eugenio Mocchegiani,Nazzarena Gasparini,Robertina Giacconi,Catia Cipriano,Elisa Muti,Marco Malavolta

doi:10.1186/1742-4933-1-5

Eugenio Mocchegiani, Nazzarena Gasparini + Show 4 more

Open Access

https://doi.org/10.1186/1742-4933-1-5

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Abstract

BackgroundWith advancing age, thymic efficiency shows progressive decline due to thymic involution allowing impaired cell-mediated immunity and the appearance of age-related diseases. The intrinsic cause of thymic involution is still undefined. Chronic inflammation and high glucocorticoids (GCs) may be involved. However, transgenic mice, with increased GC sensitivity and over expression of GC receptors, display delayed age-associated thymic involution. This fact suggests that other substances may affect thymic involution. Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. Enhanced MTs in ageing allows constant sequester of zinc ions and no subsequent zinc release leading to low zinc ion bioavailability for thymic efficiency. This sequester is very limited in very old age. Thus, we have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice.MethodsMTmRNA and IL-6mRNA (RT-PCR) in the thymus from different donors were tested. Concomitantly, TECs proliferation, zinc ion bioavailability (ratio total thymulin/active thymulin), thymulin activity and corticosterone were tested from different donors.ResultsBoth isoforms of MTmRNA and IL-6mRNA increase in old thymus coupled with low zinc ion bioavailability, reduced TECs proliferation, impaired thymulin activity and enhanced plasma corticosterone in comparison with young. Conversely, although the thymus is involuted in very old mice because of no changes in thymus weight in comparison to old mice, reduced MTmRNA, especially MT-I+II isoforms, and low IL6mRNA occur. Concomitantly, good zinc ion bioavailability, maintained TECs proliferation, satisfactory thymulin activity and reduced corticosterone are observed in very old mice.ConclusionsThe concomitant increments by high IL-6 of both MT isoforms in the thymus from old mice may be involved in thymic involution because provoking low zinc ion bioavailability, which is relevant for thymic efficiency. By contrast, the limited increments of MTs by low IL-6 induce good zinc ion bioavailability and satisfactory thymic efficiency in very old mice. Therefore, abnormal increased MTs may provoke complete thymic involution during ageing and the possible appearance of age-related diseases. If their increments are instead limited by low inflammation, healthy ageing and longevity may be reached.

Highlights

The thymus gland is a central lymphoid organ in which bone marrow-derived T cell precursors undergo a complex process of maturation and differentiation leading to migration of positively selected thymocytes to the T celldependent peripheral areas [1]
Specific GCs receptors are present both on thymocytes and Thymic Epithelial Cells (TECs) leading the thymic cells to undergo apoptosis via Fas [6]. It has been recently reported in transgenic mice with increased GC sensitivity and over expression of GC receptors, a delayed age-associated thymic involution when compared with wild-type mice
MT induction is controlled by GCs and pro-inflammatory cytokines (IL-6) [8], which increase in ageing and inflammation [9]; and high IL-6 is involved in thymic dysregulation [10]

Summary

Introduction

The thymus gland is a central lymphoid organ in which bone marrow-derived T cell precursors undergo a complex process of maturation and differentiation leading to migration of positively selected thymocytes to the T celldependent peripheral areas [1]. Specific GCs receptors are present both on thymocytes and TECs leading the thymic cells to undergo apoptosis via Fas [6] It has been recently reported in transgenic mice with increased GC sensitivity and over expression of GC receptors, a delayed age-associated thymic involution when compared with wild-type mice. These mice display a higher number of thymocytes and, surprisingly, thymic apoptosis is unaffected [7]. This fact suggests that other substances may affect thymic involution Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. We have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice

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