Overproduction of IFN‐γ and TNF‐α from Natural Killer (NK) Cells Is Associated with Abnormal NK Reactivity and Cognitive Derangement in Alzheimer's Disease

Solerte, S. B.; Cravello, Luca; Ferrari, Ettore; Fioravanti, Marisa

doi:10.1111/j.1749-6632.2000.tb05399.x

Cited by 83 publications

(53 citation statements)

References 39 publications

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“…Data are accumulating on the role that a high IL-2 production might play in immuneinflammatory mediated diseases. In humans, as reported by Solerte et al (2000) high IL-2, as well as interferon-c and tumor necrosis factora, serum levels characterise subjects affected by Alzheimer's disease. Furthermore, IL-2 increase has been associated with evolving atherosclerosis and coronary events in stable and unstable angina patients (Elkind et al 2005;Methe et al 2005).…”

Section: Discussionmentioning

confidence: 89%

Study of the Association with −330T/G IL-2 in a Population of Centenarians from Centre and South Italy

et al. 2005

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Immune response in elderly is characterised by a progressive loss of the ability to cope environmental stressors with a characteristic remodelling of cytokine network. One of the data constantly reported in literature is the decrease of IL-2 production. An IL-2 central role in the reconstitution of T cell function in vitro is largely documented. Studies on a T-->G polymorphism at -330 nt of IL-2 gene promoter region have demonstrated that T lymphocytes from 330GG homozygous subjects are able to produce in vitro higher amount of IL-2, than -330TG heterozygous or -330TT homozygous subjects. As a genetic background conditioning the maintaining of an efficient immune response would exert positive effects on healthy ageing, we have typed for 330T/G IL-2 single nucleotide polymorphism (SNP), 168 centenarians and 214 control subjects matched for age and ancestry from Centre and South Italy to check the 330GG genotype association to longevity. The statistical analysis doesn't show a significant difference of genotypic and allelic frequencies at -330 IL-2 T/G SNP among centenarians and controls. Comparing the two cohorts of subjects by extended Mantel Haenszel procedure a marginally significant trend for an increased -330TT genotype frequency was observed. Our data seem to be paradoxical considering the role attributed to a well-conserved T cell function in the successful ageing. On the other hand, in a recent study on a sample of Irish octogenarians a similar distribution of -330T/G genotype even was observed. These data suggest that a genetic background favouring an increased IL-2 production might be detrimental for longevity. On the other hand, an increase of IL-2 and other pro-inflammatory cytokine production characterise the Alzheimer's disease serum profile. All in all our data seem to suggest that reduction of -330G allele frequency might be protective for healthy ageing limiting cell mediated inflammation implied in age associated diseases.

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Section: Discussionmentioning

confidence: 89%

Study of the Association with −330T/G IL-2 in a Population of Centenarians from Centre and South Italy

et al. 2005

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“…Neuroinflammation in PD includes activation of microglia, increased secretion of cytokines and PGs, activation complement, and circulating NK cells (66). In particular, the levels of IFN-g are higher in the serum of PD patients compared with healthy donors, and freshly purified circulating NK cells from PD patients were reported to spontaneously release greater amount of IFN-g compared with healthy volunteers (67,68). The pathologic homing of NK cells to the central nervous system might help to explain the higher amount of inflammatory cytokines observed in FIGURE 5.…”

Section: Discussionmentioning

confidence: 99%

Dopamine Inhibits the Effector Functions of Activated NK Cells via the Upregulation of the D5 Receptor

Mikulak

Bozzo

Roberto

et al. 2014

The Journal of Immunology

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Several lines of evidence indicate that dopamine (DA) plays a key role in the cross-talk between the nervous and immune systems. In this study, we disclose a novel immune-regulatory role for DA: inhibition of effector functions of activated NK lymphocytes via the selective upregulation of the D5 dopaminergic receptor in response to prolonged cell stimulation with rIL-2. Indeed, engagement of this D1-like inhibitory receptor following binding with DA suppresses NK cell proliferation and synthesis of IFN-γ. The inhibition of IFN-γ production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-κB complex. Indeed, the stimulation of the D5 receptor on rIL-2–activated NK cells inhibits the binding of p50 to the microRNA 29a promoter, thus inducing a de novo synthesis of this miRNA. In turn, the increased levels of microRNA 29a were inversely correlated with the ability of NK cells to produce IFN-γ. Taken together, our findings demonstrated that DA switches off activated NK cells, thus representing a checkpoint exerted by the nervous system to control the reactivity of these innate immune effectors in response to activation stimuli and to avoid the establishment of chronic and pathologic inflammatory processes.

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“…NKCA is positively correlated with PD severity (48). Moreover, Solerte et al (52) showed that purified NK cells from blood of PD patients spontaneously secreted more IFN-g and TNF-a than did healthy donors. All of these modifications of NK cell physiology suggest that they might play a role in the pathogenesis of PD.…”

Section: Nk Cell Modifications Associated With Cns Disordersmentioning

confidence: 99%

NK Cells in Central Nervous System Disorders

Poli

Kmiecik

Domingues

et al. 2013

The Journal of Immunology

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NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells.

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Overproduction of IFN‐γ and TNF‐α from Natural Killer (NK) Cells Is Associated with Abnormal NK Reactivity and Cognitive Derangement in Alzheimer's Disease

Cited by 83 publications

References 39 publications

Study of the Association with −330T/G IL-2 in a Population of Centenarians from Centre and South Italy

Study of the Association with −330T/G IL-2 in a Population of Centenarians from Centre and South Italy

Dopamine Inhibits the Effector Functions of Activated NK Cells via the Upregulation of the D5 Receptor

NK Cells in Central Nervous System Disorders

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