Short-term zinc supplementation of zinc-deficient seniors counteracts CREMα - mediated IL-2 suppression

Abstract

Background Aging is accompanied by a dramatic decline in the interleukin (IL)-2 production capacity of human immune cells, thus making seniors more susceptible to a variety of age-related diseases. A common cause of impaired cytokine production in advanced age is a deficiency of the essential micronutrient zinc. Nevertheless, the molecular mechanisms underlying a zinc deficiency-induced decrease in IL-2 production have not yet been satisfactorily elucidated. Recent animal and in vitro data suggested that the transcription factor cAMP-responsive element modulator (CREM) $$\alpha$$ α plays a critical role in T cells´ disturbed IL-2 production in suboptimal zinc conditions. However, its role in the human aging process and the possibility of influencing this detrimental process by short-term zinc supplementation have not yet been evaluated. Results Comparing peripheral lymphocytes of 23 young and 31 elderly subjects with either high, intermediate, or deficient zinc status, we observed zinc-dependent regulation of the IL-2 production mediated by the transcription factor CREM $$\alpha$$ α . For the first time in humans, we report a mutual relationship between low zinc levels, high CREM $$\alpha$$ α expression, subsequent impaired IL-2 production, and vice versa. Remarkably, an average of only 6 days of in vivo zinc supplementation to zinc-deficient seniors was sufficient to rapidly improve zinc status, reverse CREM $$\alpha$$ α overexpression, and counteract subsequent low IL-2 production rates. Conclusions Our ex vivo and in vivo data identify zinc deficiency-mediated CREM $$\alpha$$ α overexpression as a key cellular mechanism underlying impaired IL-2 production in the elderly and point toward the use of zinc as a rapidly immune-enhancing add-on nutraceutical in geriatric therapy. Graphical abstract During the aging process, there is a progressive decrease in zinc status, which in turn leads to overexpression of the transcription factor CREM$$\mathrm{\alpha }$$ α in peripheral lymphocytes. CREMα is a negative regulator of the IL-2 gene, the overexpression of which dramatically limits adequate IL-2 production. This deleterious mechanism can be counteracted by short-term oral zinc administration, which can adjust IL-2 production in old, zinc-deficient individuals to a level similar to that of young adults.

Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution

“…It was previously shown that IFN-γ and IL-2 expression are regulated by intracellular zinc [ 9 , 11 , 18 , 22 ]; thus, we next examined the distribution of intracellular-free zinc in PPI-treated PBMC. The lysosome-free zinc concentration was determined by FluoZin-3 AM, and the cytoplasm-free zinc concentration was determined by Zinpyr-1 staining.…”

“…In order to investigate the reduced expression of IL-2 in the PPI-treated PBMC, we examined CREMα, which has been shown to inhibit IL-2 transcription in zinc deficiency [ 11 , 22 ]. The human CREM gene consists of 20 exons [ 26 , 27 ], and alternative splicing results in many different isoforms that have different, even opposite, effects on target gene expression.…”

“…Recent studies by our group have shown that zinc deficiency leads to reduced IL-2 transcription and secretion by increasing the expression of CREMα, a negative regulator of IL-2 transcription [ 11 ]. In zinc-deficient elderly patients, zinc supplementation reverses the negative effect of zinc deficiency, leading to low CREMα expression and thus normal IL-2 transcription [ 22 ].…”

Natural Compounds and Products from an Anti-Aging Perspective

“…In the case of Zn, its role in the optimal function of the immune responses appears particularly crucial, as old mice with reduced zinc levels reported an increased proinflammatory cytokines profile, such as MCP1 and IL6 in the serum, also showed increased Th1/Th17/inflammatory cytokines (IFNγ, IL17, TNFα, respectively), and decreased naïve CD4 T-cells in the mesenteric lymph nodes (MLN) [ 92 ]. The ability to enforce immunity in the elderly and to delay the immunosenescence mechanism is a leading role of these trace elements, usually in the form of metal cofactors [ 93 , 94 , 95 , 96 ].…”

Zinc in Human Health and Infectious Diseases

“…Similar results were uncovered for healthy men having a restricted zinc diet for 10 weeks, resulting in reduced IL-2R production [ 265 ]. In parallel, studies uncovered the transcription factor cAMP-responsive element modulator alpha (CREMα) to be upregulated due to zinc deficiency, leading to dampened IL-2 production [ 266 , 267 ].…”