Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREMα expression in T cells

Abstract

Background & Aims:The micronutrient zinc is essential for proper immune function. Consequently, zinc deficiency leads to impaired immune function, as seen in decreased secretion of interleukin (IL)-2 by T cells.Although this association has been known since the late 1980s, the underlying molecular mechanisms are still unknown. Zinc deficiency and reduced IL-2 levels are especially found in the elderly, which in turn are prone to chronic diseases. Here, we describe a new molecular link between zinc deficiency and reduced IL-2 expression in T cells. Methods:The effects of zinc deficiency were first investigated in vitro in the human T cell lines Jurkat and Hut-78 and complemented by in vivo data from zinc-supplemented pigs. A short-and long-term model for zinc deficiency was established. Zinc levels were detected by flow cytometry and expression profiles were investigated on the mRNA and protein level. Results:The expression of the transcription factor cAMP-responsive-element modulator (CREM ) is increased during zinc deficiency in vitro, due to increased protein phosphatase 2A (PP2A) activity, resulting in decreased IL-2 production. Additionally, zinc supplementation in vivo reduced CREM levels causing increased IL-2 expression. On epigenetic levels increased CREM binding to the IL-2 promoter is mediated by histone deacetylase 1 (HDAC1). The HDAC1 activity is inhibited by zinc. Moreover, deacetylation of the activating histone mark H3K9 was increased under zinc deficiency, resulting in reduced IL-2 expression. Conclusions:With the transcription factor CREM a molecular link was uncovered, connecting zinc deficiency with reduced IL-2 production due to enhanced PP2A and HDAC1 activity.

Profiling inflammatory cytokines following zinc supplementation: a systematic review and meta-analysis of controlled trials

“…In vitro investigation revealed that Zn deficiency increased CREMα expression (48) . IL-2 has dual effects on inflammatory pathways.…”

“…Therefore, its high expression inhibits IL-2 transcription (48) . In-vitro investigation revealed that Zn deficiency increased CREMα expression (48) .…”

“…CREMα binding site is cAMPresponsive element which is located within the IL-2 promoter. Therefore, its high expression inhibits IL-2 transcription (48) .…”

Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling

“…It has also been shown that zinc levels modulate IL‐2 expression, providing another explanation of altered CD25 expression. [ 56 ]…”

High Temperature-Induced Oxidative Stress Affects Systemic Zinc Homeostasis in Broilers by Regulating Zinc Transporters and Metallothionein in the Liver and Jejunum

“…According to the National Research Council (NRC, 1994), the requirement of zinc for broilers is 40.0 ppm; approximately 100 ppm zinc from different sources is typically added to feed to optimize animal performance [ 13 , 14 ]. The underlying mechanisms could be attributed to altered intestinal histomorphology and reduced inflammation and oxidative stress [ 15 , 16 ] resulting in improved growth of broilers. Increasing lines of evidence indicate that zinc is redistributed in animals under conditions of oxidative stress and immune challenge [ 17 , 18 ].…”