Zinc (Zn) is associated with many metal enzymes: cytoplasmic enzymes, mitochondrial enzymes, nuclear enzymes [DNA and RNA polymerase] and Golgi device enzymes. Zinc ions are also components of structural and regulatory proteins, including transcription factors, and are permanently bound to biological systems.
Zinc deficiency is a global health problem, affecting more than 10% of the population, zinc intake with meals is less than half the recommended dose, and chronic zinc deficiencies significantly increase the risk of cancer.
In the case of anticancer activity, the role of zinc in the cellular and humoral immune response is well known and a lack or insufficient immune response in cancer cells can be caused by escaping immunological monitoring. This is partly due to the fact that the tumor grows faster than the defense grows and also because cytotoxic substances are blocked by various substances secreted by the tumor {TGF-β, IL-10 and PGE2}.
Due to the increased activity of TGF -β in advanced cancer, its expression may be attenuated by administration of cytokines with antagonistic activity against this cytokine. IL-10 is an anti-inflammatory cytokine that inhibits the production of pro-inflammatory cytokines, such as IFN-γ, IL-2 interleukins, IL-3, TNF-α, or granulocyte-macrophage colony stimulating factor (GM-CSF). Cells of certain cancers, such as kidneys, are also capable of stimulating the secretion of significant amounts of the immunosuppressive PGE-2 mediator so that the tumor causes a change in the cytokine production profile in favor of a Th2 response. PGE-2 inhibits secretion of IL-2 by Th1 cells, which perform functions of stimulating an immune response, thus regulating the function of the immune system.
This mechanism is probably partly responsible for the patient’s immune dysfunction and allows cancer cells to prevent so that the tumor grows and grows in the body “unnoticed”. The immune system includes the THYME gland (growth and selection of T lymphocytes) and the bone marrow (maturation of B lymphocytes). In these organs, as a result of negative selection, 90% of T and B cells DIE during of the differentiation and the remaining 10% are immunocompetent lymphocytes.
In addition, the immune system includes the spleen, lymph nodes {for antigen recognition} and various mucosal tissues associated with mucosa, such as {1 muc mucosa-associated lymphatic tissue (MALT), {2 skin skin-associated lymphatic tissue (SALT), Ut 3 g gut-associated lymphatic tissue (GALT), Al 4 nasal-associated lymphatic tissue (NALT) {5 bron bronchus-associated lymphatic tissue (BALT). The main function of the immune system is to monitor mutated, damaged and old cells that can lead to the development of cancer and autoimmune diseases. The body has a powerful arsenal for the effective destruction of cancer cells, consisting mainly of natural killer cells (NK), Tc lymphocytes (cytotoxic lymphocytes), macrophages, granulocytes, cytokines secreted by immune cells, including immune cells.
The immune system is particularly sensitive to changes in zinc levels. In fact, it seems that every response is somehow directly or indirectly related to zinc. A cytotoxic effect is known to result from the secretion into the environment of cytokines, free radicals and enzymes and substances that damage cell membranes. Lymphocyte-derived cytokines play a key role in anti-cancer immunity. They are synthesized and released as a cataract and include interleukins, interferons, TNF-α, β, and growth factors (GM-CSF), specific as well as non-specific immunity in various ways. In vitro zinc deficiency inhibits granulocyte uptake, ROS production, chemotaxis, and phagocytosis where pathogens are destroyed by active zinc-dependent NADPH (inhibits both zinc deficiency and surpluses). cells also depend on zinc. In vivo, low serum zinc levels reduce granulocyte count, NK cell count and macrophage phagocytic capacity, while zinc deficiency increases the production of proinflammatory cytokines IL-1β, IL-6 and TNF-α.
However, zinc exerts its strongest effect on the immune system through Th lymphocytes. Lymphocytes include Th1 and Th2 cells. The reduced zinc content in the cell disturbs the balance between Th1 and Th2 to Th2.
Zinc supplementation eliminates this imbalance, significantly increasing the IFN-γ released by peripheral blood mononuclear cells, as IFN-γ is the major factor having antiviral, immunoregulatory and anti-cancer properties. , IL-12, IL-18, IFN-γ and TNF-α, play the most important role in anti-cancer defense.
The best known effects of IL-12 include enhancing the activity of NK cells, shifting the Th1 / Th2 balance in favor Th1 causing differentiation induction of IFN-γ secretion by Th1 and NK cells. Increased interferon production negatively affects the activity of cells with Th2 phenotype and reduces the amount of cytokine release. Th2 lymphocytes cooperate with Th1 cells in the anti-cancer defense, supporting the synthesis of antibodies by B lymphocytes through IL-4, IL-5 and IL-6. Th1 cells activate macrophages via IFN-γ and activate NK cells via IL-2. In addition, Th1 cells instantly kill cancer cells and inhibit their proliferation.
As mentioned above, zinc has the strongest effect on the immune system through T lymphocytes. T-cell maturation takes place in the thymus gland and is dependent on thymulin, which is a peptide hormone secreted by thymic endothelial cells. In addition, zinc regulates the morphological and physiological integrity of the thymus by acting as a cofactor of thymulin by regulating the differentiation of mature T cells in the thymus gland and the function of maturation of T cells in the peripheral blood.
Zinc deficiency is also responsible for atrophy of the thymus gland and the consequent cessation of lymphocyte growth. Small changes in serum zinc concentration reduce the level of T cells. In addition, thymulin induces the expression of IL-2 receptors and regulates the production of cytokines causing CD8 cell proliferation in conjunction with IL-2. Therefore, zinc deficiency leads to a decrease in the number of T and B lymphocytes in both the thymus gland and the bone marrow, which leads to increased susceptibility to infection and weakened defenses.
Zinc supplementation at 20 mg / day of zinc for five weeks in children with zinc deficiency was found to increase CD4 + and CD8 + cell counts and in the elderly, 48-day supplementation led to an increase in Th lymphocytes.
Other research has shown that zinc supplementation (5 mg / kg) for four weeks significantly increased the number of NK cells involved in cancer prevention processes and zinc is essential for their activation. IL-17, as a pleiotropic cytokine, can stimulate tumor growth, as it has been shown to promote the growth of cancer cells through pro-inflammatory and pro-angiogenic activity.
STAT3-mediated IL-6 activation and Th17 in vitro cell growth were inhibited by Zn by disruption of STAT3 binding to JAK2 kinase (Janus kinase-2], and there is ample evidence to support the anti-cancer effect of lymphocytes. Th17 seems to depend to a large extent on the progression of the disease (which has a different role in the early and late stages), as well as on the origin of the cancer and the role of inflammatory processes and angiogenesis in its pathogenesis.
Low levels of zinc lead to a reduction in the total number of B cells and their precursors, as well as to the production of antibodies. However, the changes in B-cell maturation are insignificant. Changes in B cell count are most likely caused by apoptosis. Glucocorticoids secreted in response to zinc deficiency cause increased apoptosis in immature B and T lymphocytes in the bone marrow and thymus gland.
In addition to the positive effect of zinc on immune cells, an adverse effect has also been observed: in some cases where Zn 2+ ions promote the proliferation of pathogens. Excess zinc can be dangerous due to its immunosuppressive effect. At high doses, it may exert an immunosuppressive effect by inhibiting lymphocyte function and IFN-γ production.
This immunosuppressive effect of zinc may have a new therapeutic application in autoimmune diseases, such as rheumatoid arthritis or rheumatoid arthritis, selective suppression of lymphocyte function is beneficial.
SOURCE: Nutrients 2019.
