Magnesium in Infectious Diseases in Older People.

Reduced magnesium (Mg) intake is a frequent cause of deficiency with age together with reduced absorption, renal wasting, and polypharmacotherapy. Chronic Mg deficiency may result in increased oxidative stress and low-grade inflammation, which may be linked to several age-related diseases, including higher predisposition to infectious diseases. Mg might play a role in the immune response being a cofactor for immunoglobulin synthesis and other processes strictly associated with the function of T and B cells. Mg is necessary for the biosynthesis, transport, and activation of vitamin D, another key factor in the pathogenesis of infectious diseases. The regulation of cytosolic free Mg in immune cells involves Mg transport systems, such as the melastatin-like transient receptor potential 7 channel, the solute carrier family, and the magnesium transporter 1 (MAGT1). The functional importance of Mg transport in immunity was unknown until the description of the primary immunodeficiency XMEN (X-linked immunodeficiency with Mg defect, Epstein-Barr virus infection, and neoplasia) due to a genetic deficiency of MAGT1 characterized by chronic Epstein-Barr virus infection. This and other research reporting associations of Mg deficit with viral and bacterial infections indicate a possible role of Mg deficit in the recent coronavirus disease 2019 (COVID-19) and its complications. In this review, we will discuss the importance of Mg for the immune system and for infectious diseases, including the recent pandemic of COVID-19.

The COVID-19 pandemic: is there a role for magnesium? Hypotheses and perspectives.

More and more studies are accumulating about COVID-19. Some aspects of the pathogenesis of the disease recall events occurring in Mg deficiency, such as a drop of T cells, increased plasma concentration of inflammatory cytokines, and endothelial dysfunction. We hypothesize that a low Mg status, which is rather common, might foment the transition from mild to critical clinical manifestations of the disease. Epidemiological, clinical, and fundamental research is needed to clarify the potential role of Mg deficiency in COVID-19.

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαß+ T cells (αßDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Burning magnesium, a sparkle in acute inflammation: gleams from experimental models.

Magnesium contributes to the regulation of inflammatory responses. Here, we focus on the role of magnesium in acute inflammation. Although present knowledge is incomplete to delineate an accurate scenario and a schedule of the events occurring under magnesium deficiency, it emerges that low magnesium status favors the induction of acute inflammation by sensitizing sentinel cells to the noxious agent, and then by participating to the orchestration of the vascular and cellular events that characterize the process.

Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D.

The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg(2+) causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.

Magnesium and calcium deficiencies additively increase zinc concentrations and metallothionein expression in the rat liver.

Mg deficiency increases the concentration of Zn in the liver. We investigated the effect of Mg deficiency on the expression of Zn-regulating factors such as Zn transporters and metallothionein (MT) in the rat liver. Because Ca deficiency alleviates some of the effects of Mg deficiency, we also investigated the interactions associated with Ca and Mg deficiencies. Growing male rats were given a control diet, a Mg-deficient diet, a Ca-deficient diet and a Mg- and Ca-deficient diet for 3 weeks. Mg and Ca deficiencies additively increased the mRNA levels of MT-1 and MT-2, the MT protein concentration and the concentration of Zn in the liver. The hepatic mRNA level of Zip14 increased with Mg deficiency but not with Ca deficiency. The dietary treatments did not affect the mRNA levels of other Zn transporters such as Zip1, Zip5, ZnT1, ZnT5 and ZnT6 in the liver. Ca deficiency was found to decrease the amount of femoral Zn and increase serum Zn concentration. This did not occur in the case of Mg deficiency. These results suggest that Mg deficiency enhances hepatic Zn uptake by the up-regulation of Zip14 expression and increases hepatic Zn concentration, leading to the enhancement of MT expression. Ca deficiency causes a transfer of Zn from the bone to the liver, which increases hepatic Zn concentration and, in turn, up-regulates the expression of MT. Because Mg and Ca deficiencies increase hepatic Zn concentration and increase MT expression by different mechanisms, their effects are additive.

Magnesium deficiency induces the emergence of mast cells in the liver of rats.

Mast cells, multifunctional effector cells of the immune system, are implicated in the pathogenesis of hepatic steatosis and fibrosis. Magnesium (Mg) deficiency was reported to increase triglyceride concentration in the liver, and to exacerbate the collagen deposition induced by carbon tetrachloride in the liver. Although Mg deficiency increases mast cells in the small intestine, the kidney and bone marrow, the effect of Mg deficiency on mast cells has not been clarified in the liver. We examined the emergence of mast cells in the liver of Sprague-Dawley rats given an Mg-deficient diet. Rats were fed a control diet or an Mg-deficient diet for 4 wk. Mg deficiency increased the levels of mRNA known to be expressed by mast cells in the liver; the mRNA of α- and ß-chain high-affinity immunoglobulin E receptor (FcεR1α, FcεR1ß), and the mRNA of mast cell protease 1 (Mcpt1), and mast cell protease 2 (Mcpt2). Histological observation showed that some mast cells were locally distributed around portal triads in the Mg-deficient group but mast cells were scarcely found in the control group. These results clearly indicate that Mg deficiency induces the emergence of mast cells around portal triads of the liver in Sprague-Dawley rats.

Hypomagnesemia and inflammation: clinical and basic aspects.

In recent years, increasing awareness of hypomagnesemia has resulted in clinical trials that associate this mineral deficiency with diabetes, metabolic syndrome, and drug therapies for cancer and cardiovascular diseases. However, diagnostic testing for tissue deficiency of magnesium still presents a challenge. Investigations of animal and cellular responses to magnesium deficiency have found evidence of complex proinflammatory pathways that may lead to greater understanding of mediators of the pathobiology in neuronal, cardiovascular, intestinal, renal, and hematological tissues. The roles of free radicals, cytokines, neuropeptides, endotoxin, endogenous antioxidants, and vascular permeability, and interventions to limit the inflammatory response associated with these parameters, are outlined in basic studies of magnesium deficiency. It is hoped that this limited review of inflammation associated with some diseases complicated by magnesium deficiency will prompt greater awareness by clinicians and other health providers and in turn increase efforts to prevent and treat this disorder.

The role of magnesium deficiency in cardiovascular and intestinal inflammation.

Hypomagnesemia continues to cause difficult clinical problems, such as significant cardiac arrhythmias where intravenous magnesium therapy can be lifesaving. Nutritional deficiency of magnesium may present with some subtle symptoms such as leg cramps and occasional palpitation. We have investigated dietary-induced magnesium deficiency in rodent models to assess the pathobiology associated with prolonged hypomagnesemia. We found that neuronal sources of the neuropeptide, substance P (SP), contributed to very early prooxidant/proinflammatory changes during Mg deficiency. This neurogenic inflammation is systemic in nature, affecting blood cells, cardiovascular, intestinal, and other tissues, leading to impaired cardiac contractility similar to that seen in patients with heart failure. We have used drugs that block the release of SP from neurons and SP-receptor blockers to prevent some of these pathobiological changes; whereas, blocking SP catabolism enhances inflammation. Our findings emphasize the essential role of this cation in preventing cardiomyopathic changes and intestinal inflammation in a well-studied animal model, and also implicate the need for more appreciation of the potential clinical relevance of optimal magnesium nutrition and therapy.

Efeitos da deficiência de cobre, zinco e magnésio sobre o sistema imune de crianças com desnutrição grave: [revisão] / Effects of copper, zinc and magnesium deficiency on the immune system of severely malnourished children: [review]

OBJETIVO: Esclarecer as repercussões da deficiência de cobre, zinco e magnésio sobre o sistema imune de crianças desnutridas graves. FONTES DE DADOS: Foi realizada revisão bibliográfica mediante consulta às bases de dados Pubmed Medline, Lilacs e SciELO, selecionando-se publicações científicas recentes, da última década, e representativas do tema por meio dos descritores: desnutrição infantil, cobre, zinco, magnésio e sistema imune. SÍNTESE DE DADOS: Os micronutrientes são compostos orgânicos essenciais. Além de sua função regulatória, atuam de maneira decisiva na modulação da resposta imune. Sua deficiência pode ocorrer devido à ingestão inadequada ou associada a doenças específicas. Quando associada à desnutrição, a multideficiência de minerais pode acarretar disfunções imunológicas e aumento na suscetibilidade a infecções, afetando gravemente a eficácia de intervenções terapêuticas. Cobre, zinco e magnésio atuam como cofatores de enzimas responsáveis tanto por diversas atividades metabólicas como na resposta imune inata e adquirida, além do papel importante na maturação dos tecidos e células linfoides. Sua deficiência acarreta neutropenia e linfopenia, comprometendo a imunocompetência. CONCLUSÕES: As alterações ocasionadas pelos déficits séricos dos minerais cobre, zinco e magnésio comprometem o funcionamento do sistema imune, levando à imunossupressão. A reposição desses elementos no manejo da desnutrição grave, como preconizada pela Organização Mundial da Saúde, é essencial, uma vez que tais alterações podem ser reversíveis.

OBJECTIVE: To report the effects of the deficiency of copper, zinc and magnesium on the immune system of severely malnourished children. DATA SOURCE: A literature review was performed by consulting the databases Pubmed Medline, Lilacs and SciELO, using the descriptors: child malnutrition, copper, zinc, magnesium and immune system. Representative studies published during the last decade were chosen. DATA SYNTHESIS: Micronutrients are essential organic compounds. Besides their regulatory function, the minerals act on the modulation of the immune response. Their deficiency may be due to inadequate intake or associated with specific diseases. When combined with malnutrition, a multimineral deficiency can cause immune dysfunction and increased susceptibility to infections, altering the effectiveness of therapeutic interventions. Copper, zinc and magnesium act as co-factors of both enzymes responsible for several metabolic activities and associated to the innate and acquired immune response. These minerals also play an important role in the maturation of lymphoid tissues and cells. Their deficiency causes neutropenia and lymphopenia, decreasing the immunocompetence. CONCLUSIONS: Deficits of serum copper, zinc and magnesium affect the function of the immune system, leading to immunosuppression. The replacement of these elements in the management of severe malnutrition, as recommended by the World Health Organization, is essential, since such changes may be reversible.

Effect of nutrient deficiencies on in vitro Th1 and Th2 cytokine response of peripheral blood mononuclear cells to Plasmodium falciparum infection.

BACKGROUND: An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies. METHODS: Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status. RESULTS: The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-gamma response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-gamma production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status. CONCLUSIONS: The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status.

Alterations in early cytokine-mediated immune responses to Plasmodium falciparum infection in Tanzanian children with mineral element deficiencies: a cross-sectional survey.

BACKGROUND: Deficiencies in vitamins and mineral elements are important causes of morbidity in developing countries, possibly because they lead to defective immune responses to infection. The aim of the study was to assess the effects of mineral element deficiencies on early innate cytokine responses to Plasmodium falciparum malaria. METHODS: Peripheral blood mononuclear cells from 304 Tanzanian children aged 6-72 months were stimulated with P. falciparum-parasitized erythrocytes obtained from in vitro cultures. RESULTS: The results showed a significant increase by 74% in geometric mean of TNF production in malaria-infected individuals with zinc deficiency (11% to 240%; 95% CI). Iron deficiency anaemia was associated with increased TNF production in infected individuals and overall with increased IL-10 production, while magnesium deficiency induced increased production of IL-10 by 46% (13% to 144%) in uninfected donors. All donors showed a response towards IL-1beta production, drawing special attention for its possible protective role in early innate immune responses to malaria. CONCLUSIONS: In view of these results, the findings show plasticity in cytokine profiles of mononuclear cells reacting to malaria infection under conditions of different micronutrient deficiencies. These findings lay the foundations for future inclusion of a combination of precisely selected set of micronutrients rather than single nutrients as part of malaria vaccine intervention programmes in endemic countries.

Effect of hypomagnesemia on allogeneic activation in mice.

INTRODUCTION: Magnesium (Mg) plays an essential role in a wide range of fundamental cellular reactions. It has been reported that in rodents Mg-deficient diet-induced hypomagnesemia results in an early inflammation. We have previously shown that chronic severe hypomagnesemia was associated neither with endothelial cell activation nor with an inflammatory process which are crucial in the allograft rejection process. T cell allogeneic stimulation activates the phosphatase calcineurin which triggers the signaling pathways leading to IL-2 synthesis and lymphocyte proliferation. Full activation of calcineurin requires Mg. Surveys suggest that a significant number of people consume less Mg than the international dietary reference intakes leading to hypomagnesemia in 2.5% to 15% of the general population. OBJECTIVE: The aim of the study was to investigate the effects of hypomagnesemia on lymphocyte allogeneic activation and proliferation in a murine model of dietary-induced hypomagnesemia. METHODS: C57BL/6J (H-2(b), Mls(b)) mice were given normal Mg-containing diet (1400 ppm Mg, control mice), or synthetic Mg-deficient diets containing either 50 ppm Mg or 150 ppm Mg for 28 days. Serum Mg levels were determined at days 5, 14 and 28. In parallel, complete urine and faeces were collected by using metabolic cages during a 24 h period for Mg determinations. Splenocytes from C57BL/6 mice fed either normal diet or 50 ppm Mg-diet were used as responder cells in mixed lymphocyte reaction (MLR) performed with splenocytes from C3H/He mice (H-2(k), Mls(IIa)) and C57BL/6 mice fed normal diet as stimulators for allogeneic and isogeneic conditions, respectively. TGF-beta and IL-2 productions were quantified in the supernates of mixed splenocytes cultures. 3x10(6) splenocytes from mice fed 50 ppm Mg-diet were used for calcineurin activity determination at day 28. RESULTS: In mice fed 150 ppm Mg-diet, moderate hypomagnesemia was observed from day 5 to day 28. Oral supplementation with Mg pidolate (5 or 20 mg Mg/kg/day) could not restore normal serum Mg levels. Serum Mg concentration early decreased in mice fed 50 ppm Mg-diet to achieve stabilized severe hypomagnesemia at days 14 and 28. Urine Mg concentration early dramatically fell down then stabilized in mice fed Mg-deficient diets. In MLR performed at day 28 with splenocytes from mice fed 50 ppm Mg-diet, proliferation and IL-2 production in allogeneic conditions were similar to control mice. No TGF-beta production was detected in any group. Lastly, calcineurin activity measured at day 28 was significantly lower in splenocyes from mice fed 50 ppm Mg-diet than in mice fed control diet. CONCLUSION: Mg-deficiency does not alter splenocyte allogeneic activation and proliferation and IL-2 production in vitro, although it partially inhibits calcineurin activity. We hypothesize that the remaining activity is sufficient for IL-2 gene normal activation. Alternatively, Mg-deficiency may trigger other signaling pathways leading to IL-2 production.

Exercise, magnesium and immune function.

Physical exercise may deplete magnesium, which together with a marginal dietary magnesium intake may impair energy metabolism, muscle function, oxygen uptake and electrolyte balance. Consequently, the ability to perform physical work may be compromised. Many aspects of immune function can be depressed temporarily by either a single bout of very severe exercise or a longer period of excessive training. Although the disturbance is usually quite transient, it can be sufficient to allow a clinical episode of infection, particularly upper respiratory tract infections. However, regular and moderate exercise has been reported to improve the ability of the immune system to protect the host from infection. Magnesium also has a strong relation with the immune system in both non specific and specific immune responses and magnesium deficit has been shown to be related to impaired cellular and humoral immune function. Magnesium deficiency leads to immunopathological changes that are related to the initiation of a sequential inflammatory response. Although in athletes magnesium deficiency has not been investigated regarding alterations in the immune system, the possibility exists that magnesium deficiency could contribute to the immunological changes observed after strenuous exercise.

[Study of anti-inflammatory activity of some organic and inorganic magnesium salts in rats fed with magnesium-deficient diet].

The purpose of the present research was comparative study of anti-inflammatory action of some Mg salts in rats fed with Mg-deficient diet. It was shown in our study that administration of Mg L-aspartate with pyridoxine leads to higher compensation of Mg deficiency in rats with diet-induced Mg depletion as compared with other Mg supplementations. According to the Mg deficiency correction rate Mg salts may be ranged in the following order: Mg L-aspartate with pyridoxine > or = Mg chloride with pyridoxine > or = Mg lactate with pyridoxine > or = Mg L-aspartate > Mg chloride > Mg orotate. In our study administration of Mg salts resulted in decreased number of blood leukocytes, reduced peripheral vasodilation visible in the external ear, decreased spleen weight, and as consequences in reduced inflammatory and immunological response. According to correction rate of the inflammatory response Mg salts may be ranged in the following order: Mg orotate > or = Mg chloride > or = Mg chloride with pyridoxine > or = Mg L-aspartate > or = MgL-aspartate with pyridoxine > or = Mg lactate with pyridoxine.

Morphological and immune response alterations in the intestinal mucosa of the mouse after short periods on a low-magnesium diet.

The importance of Mg for the immune function is well recognized; however, there is no information available about the effect of Mg intake on the modulation of local immune response in the intestine. Thus, in the present study the hypothesis that short periods of Mg deprivation can affect intestinal mucosa and local immune response was tested. For this purpose, OF1 female mice were fed a semipurified diet (1000 mg Mg/kg diet). For 3 d before immunization and 1 d after, half of the animals were fed a Mg-deficient diet (30 mg Mg/kg diet), three immunizations per os were performed every 3 weeks with Escherichia coli producing the CS31A capsule-like protein (1010 or bacteria per animal). Mice were killed 10 d after the last immunization. The level of specific anti CS31A immunoglobulin (Ig) G and IgA in the serum and secretory IgA in the intestinal secretions and faeces were measured by ELISA. The results indicated that administration of a high dose of immunogen with a low-Mg diet led to lower specific IgA levels in the intestinal mucus and serum. Administration of a low dose of immunogen with a low-Mg diet led to lower IgA and IgG levels in the serum and secretory IgA coproantibodies. To assess alterations of intestinal mucosa caused by a low-Mg diet for a short period, histological and scanning electron microscopy analyses were performed on samples from mice (not submitted to the vaccination protocol) after 3 d on the Mg-deficient diet. These analyses showed several alterations, suggesting perturbations in the growth of the intestinal mucosa. These changes were accompanied by modifications in the expression of several genes involved in cell growth and stress response. From this present work, it may be concluded that short periods of Mg deprivation can affect the intestinal mucosa and local immune response of the intestine.

Protective effect of calcium deficiency on the inflammatory response in magnesium-deficient rats.

BACKGROUND: Previous studies indicated that dietary Mg-deficiency in rats results in a marked pro-inflammatory effect. Since magnesium (Mg) frequently acts as a natural calcium (Ca) antagonist, the possibility exists that the pro-inflammatory effect of Mg-deficiency may be a consequence of a reduced extracellular Mg(2+)/Ca(2+) antagonism. AIM OF THE STUDY: Thus, the aim of the study was to assess whether dietary Ca-deficiency improves the abnormal inflammatory response of Mg-deficient rats. MATERIALS AND METHODS: Weaning male Wistar rats were randomly divided into 4 groups according to the dietary Mg and Ca as follows: Mg-adequate Ca-adequate (control), Mg-adequate Ca-deficient, Mg-deficient Ca-adequate, Mg-deficient Ca-deficient. Animals were fed the appropriate diets for 8 days. RESULTS: Mg-deficient Ca-adequate rats as compared to controls displayed the usual decrease in plasma Mg, whereas the plasma Ca concentration was unaffected. The classical symptoms of inflammation including hyperemia, increased number of blood leukocytes and increased spleen weight were observed. In addition, these animals also showed an increase in heart lipid peroxidation and in plasma triglyceride concentration. In Mg-deficient rats, Ca-deficiency induced hypocalcemia and offered a significant protection against the pro-inflammatory effect of Mg-deficiency. This was evidenced by lower inflammation scores, prevention of leukocytosis and of spleen enlargement. The protective effects of Ca-deficiency on the inflammatory response in Mg-deficiency was accompanied by significant reduction in lipid peroxidation and by a normalization of plasma triglyceride concentration. CONCLUSION: All together, the results suggest that Ca is implicated in the inflammatory response of experimental Mg-deficiency and that oxidative stress and hypertriglyceridemia are the results of the acute phase response following Mg-deficiency in rats.

Increased phagocytosis and production of reactive oxygen species by neutrophils during magnesium deficiency in rats and inhibition by high magnesium concentration.

Recent studies underline the importance of the immunoinflammatory processes in the pathology of Mg deficiency. Neutrophils possess a superoxide anion-generating NADPH oxidase and its inappropriate activation may result in tissue damage. The aim of the present study was to assess the effect of experimental Mg deficiency in the rat on polymorphonuclear leucocytes (PMN) activity and the role of increasing extracellular Mg. Weaning male Wistar rats were fed either a Mg-deficient or a control diet for 8 d. In Mg-deficient rats, the characteristic inflammatory response was accompanied by a marked increase in the number of PMN. Higher plasma interleukin 6 and NO concentrations and increased lipid peroxidation in the heart were found in Mg-deficient rats as compared with control rats. As shown by chemiluminescence studies, basal neutrophil activity from Mg-deficient rats was significantly elevated when compared with neutrophils from control rats. Moreover, the chemiluminescence of PMN from Mg-deficient rats was significantly higher than that of control rats following phorbol myristate acetate or opsonized zymosan activation. PMN from Mg-deficient rats also showed an increased activity of phagocytosis in comparison with neutrophils from control animals. Increasing extracellular Mg concentration in the incubating medium of PMN (0.8 v. 8.0 mM) decreased the chemiluminescence activity of PMN from control rats following opsonized zymosan activation. Chemiluminescence activities of PMN from Mg-deficient rats following phorbol myristate acetate or opsonized zymosan challenge were also decreased by high extracellular Mg concentration. From this work, it appears that PMN activation is an early consequence of Mg deficiency and that high extracellular Mg concentration inhibits free radicals generation.