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Tamas Fulop

Publications and source records attributed to Tamas Fulop.

13 recordsLinked to original sources
PubMed2006

Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions.

It has been shown that the functions and the rescue from apoptosis by proinflammatory mediators of polymorphonuclear leukocytes (PMN) tend to diminish with aging. Here, we investigated the role of protein tyrosine phosphatases (PTP), especially Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1), in the age-related, altered PMN functions under granulocyte macrophage-colony stimulating factor (GM-CSF) stimulation. The inhibition of PTP suggested a differential effect of GM-CSF on phosphatase activity in modulating PMN functions with aging. The down-regulation of phosphatase activity of immunopurified SHP-1 from lipid rafts of PMN of young donors was found significantly altered at 1 min of stimulation with aging. In young donors, SHP-1 is displaced from lipid rafts at 1 min of stimulation, whereas in the elderly, SHP-1 is constantly present. We assessed in PMN lipid rafts the phosphorylation of tyrosine and serine residues of SHP-1, which regulates its activity. We observed an alteration in the phosphorylation of tyrosine and serine residues of SHP-1 in PMN of elderly subjects, suggesting that GM-CSF was unable to inhibit SHP-1 activity by serine phosphorylation. GM-CSF activates Lyn rapidly, and we found alterations in its activation and translocation to the lipid rafts with aging. We also demonstrate that SHP-1 in the PMN of elderly is constantly recruited to Lyn, which cannot be relieved by GM-CSF. In contrast, in the young, the resting recruitment could be relieved by GM-CSF. Our results suggest an alteration of the SHP-1 modulation by GM-CSF in lipid rafts of PMN with aging. These alterations could contribute to the decreased GM-CSF effects on PMN.

Adult↗
PubMed2005

Age-related decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1's free sulfhydryl groups.

The aim of this study was to evaluate the antioxidant activity of HDL with aging and to investigate the implication of PON1 in this process. The study involved 54 healthy subjects distributed in two age groups, young (20-25 years) and elderly (65-85 years). Lipid peroxidation was induced by *OH and O2*- oxygen free radicals produced by gamma-radiolysis of water. LDL oxidation was followed by the measurement of conjugated diene (CD), lipid peroxide (LP) and malondialdehyde (MDA) formation. PON1 was purified separately from young (Y-PON1) and elderly subjects (E-PON1). PON1 activity and structure was followed by measurement of PON1 paraoxonase (p.ase) activity, titration of the SH groups, and electrophoretic mobility by SDS-PAGE. Our results show a significant decrease in the HDL antioxidant activity: percentage of protection against CD formation=27.70% (p<0.01) for E-HDL versus 73.08% (p<0.001) for Y-HDL. Moreover, E-PON1 showed a lower antioxidant activity when compared to Y-PON1 47.08% versus 78.14%, respectively (p<0.0001). Exposition of PON1 to *OH and O2*- oxygen free radicals induced a significant decrease in PON1 p.ase activity as well as a reduction in the number of PON1's free sulfhydryl groups. Moreover, our results show a close association between PON1's free sulfhydryl groups and its capacity to protect LDL against lipid peroxidation. There was a significant decrease in the number of free sulfhydryls between Y-PON1 and E-PON1 with respect to cysteine-284 amino acid residues (p<0.0092).

Adult↗
PubMed2005

The role of the MAPK pathway alterations in GM-CSF modulated human neutrophil apoptosis with aging.

BACKGROUND: Neutrophils represent the first line of defence against aggressions. The programmed death of neutrophils is delayed by pro-inflammatory stimuli to ensure a proper resolution of the inflammation in time and place. The pro-inflammatory stimuli include granulocyte-macrophage colony-stimulating factor (GM-CSF). Recently, we have demonstrated that although neutrophils have an identical spontaneous apoptosis in elderly subjects compared to that in young subjects, the GM-CSF-induced delayed apoptosis is markedly diminished. The present study investigates whether an alteration of the GM-CSF stimulation of MAPKs play a role in the diminished rescue from apoptosis of PMN of elderly subjects. METHODS: Neutrophils were separated from healthy young and elderly donors satisfying the SENIEUR protocol. Neutrophils were stimulated with GM-CSF and inhibitors of the MAPKinase pathway. Apoptosis commitment, phosphorylation of signaling molecules, caspase-3 activities as well as expression of pro- and anti-apoptotic molecules were performed in this study. Data were analyzed using Student's two-tailed t-test for independent means. Significance was set for p </= 0.05 unless stated otherwise. RESULTS: In this paper we present evidence that an alteration in the p42/p44 MAPK activation occurs in PMN of elderly subjects under GM-CSF stimulation and this plays a role in the decreased delay of apoptosis of PMN in elderly. We also show that p38 MAPK does not play a role in GM-CSF delayed apoptosis in PMN of any age-groups, while it participates to the spontaneous apoptosis. Our results also show that the alteration of the p42/p44 MAPK activation contributes to the inability of GM-CSF to decrease the caspase-3 activation in PMN of elderly subjects. Moreover, GM-CSF converts the pro-apoptotic phenotype to an anti-apoptotic phenotype by modulating the bcl-2 family members Bax and Bcl-xL in PMN of young subjects, while this does not occur in PMN of elderly. However, this modulation seems MAPK independent. CONCLUSION: Our results show that the alteration of p42/p44 MAPK activation contributes to the GM-CSF induced decreased PMN rescue from apoptosis in elderly subjects. The modulation of MAPK activation in PMN of elderly subjects might help to restore the functionality of PMN with aging.

Journal Article↗
PubMed2005

Elastin peptides induced oxidation of LDL by phagocytic cells.

The degradation products of one of the major component of vascular wall, elastin, have several important biological activities. Elastin peptides (KE) are mostly generated during vascular aging and the atherosclerotic process. They induce free radical and proteases production from cells, which are the major components of the atherosclerotic process. In the present study, we investigated whether the interaction between elastin peptides and neutrophils as well as monocytes contributes to low density lipoproteins (LDL) oxidation, being one of the most important initiator of the chronic inflammatory process contributing to the development of atherosclerosis. Here, we present data on the link between the elastin degradation products and LDL oxidation by the chemotactically attracted neutrophils and monocytes. The KE as well as the active epitope, the hexapeptide VGVAPG is able, in a differential concentration and time dependence, to induce the oxidation of LDL. KE is able to induce via the production of free radicals by neutrophils the oxidation of LDL very rapidly and in higher concentration compared to monocytes. These effects of KE are occurring through the stimulation of the 67 kDa elastin-laminin receptor (ELR), as demonstrated by the uncoupling effect of lactose. In our present study, the HDL was able to decrease the LDL oxidation by KE. This is a new mechanism by which elastin peptides might participate in the initiation and progression of the atherosclerotic process.

Aging↗
PubMed2005

Dysregulation of T-cell function in the elderly : scientific basis and clinical implications.

The function of the immune system is to maintain body integrity by defending against infections, cancers, autoimmune diseases and inflammation-related chronic diseases. The immune response is known to become defective with aging, leading to decreased longevity and appearance of age-related disease. The most important changes occur in T-cell immunity, and are manifested particularly as altered clonal expansion of cells of limited antigen specificity. The causes of these alterations are multifactorial, and include thymic involution, T-cell subset changes and signal transduction alterations. The clinical consequences of these changes are not well defined, except for their extremely important negative impact on defence against infections, especially by new pathogens, and decreased responses to vaccination. Considering the public health consequences of decreased immune competence in old age, strategies for immune response modulation are desirable to decrease the health burden for the elderly and improve their quality of life.

Aged↗
PubMed2004

Study of factors influencing the decreased HDL associated PON1 activity with aging.

Paraoxonase (PON1) is principally complexed to HDL and is responsible, at least in part, for its antioxidant properties. PON1 activity decreases in several pathologies associated with atherosclerosis. The aim of this study was to investigate the PON1 activity and factors influencing its activity as a function of age. One hundred and twenty nine healthy subjects aged between 22 and 89 years were recruited for the study. We found that serum PON1 activity significantly decreased with age (r=-0.38, p<0.0001) while its arylesterase activity as well as its concentration in the serum did not change significantly. HDL concentrations remained unchanged with age, however, Apo A1 concentration showed a slight negative but significant correlation with age (r=-0.19, p<0.027). Moreover, the total cholesterol concentration was positively and significantly correlated with age (r=0.40, p<0.001). Thus, our results suggest that the decrease in PON1 activity cannot be explained by the decrease in Apo A1 concentrations with age. HDL from elderly subjects was more susceptible to oxidation than HDL from young subjects measured by higher lipid peroxidation rate. Thus, the decrease in PON1 activity may contribute to this increased susceptibility of HDL to oxidation with aging. Altogether our results suggest that the decrease in PON1 activity may be related to the development of oxidative stress conditions with aging and the increased HDL susceptibility to oxidation in elderly subjects.

Adult↗
PubMed2004

Signal transduction and functional changes in neutrophils with aging.

It is well known that the immune response decreases during aging, leading to a higher susceptibility to infections, cancers and autoimmune disorders. Most widely studied have been alterations in the adaptive immune response. Recently, the role of the innate immune response as a first-line defence against bacterial invasion and as a modulator of the adaptive immune response has become more widely recognized. One of the most important cell components of the innate response is neutrophils and it is therefore important to elucidate their function during aging. With aging there is an alteration of the receptor-driven functions of human neutrophils, such as superoxide anion production, chemotaxis and apoptosis. One of the alterations underlying these functional changes is a decrease in signalling elicited by specific receptors. Alterations were also found in the neutrophil membrane lipid rafts. These alterations in neutrophil functions and signal transduction that occur during aging might contribute to the significant increase in infections in old age.

Aging↗
PubMed2004

Engineering anticancer T cells for extended functional longevity.

Like other somatic cells, human T lymphocytes have a finite replicative capacity in vitro, and, by implication and consistent with the limited data available, in vivo as well. An accumulation of dysfunctional T cells may be detrimental under conditions of chronic antigenic stress (chronic infection, cancer, autoimmunity). Using T cells from young donors to model the process of T cell clonal expansion in vitro under these conditions reveals age-associated increasing levels of oxidative DNA damage and microsatellite instability (MSI), coupled with decreasing DNA repair capacity, telomerase induction and telomere length, decreased levels of expression of the T cell costimulator CD28 and consequently reduced secretion of the T cell growth factor interleukin-2 (IL-2). However, data from similar experiments using T cell clones (TCCs) derived from extremely healthy very elderly donors ("successfully aged") indicate that DNA repair is better maintained, MSI less prevalent, and (already short) telomere lengths are maintained. Nonetheless, oxidative DNA damage is seen to the same extent, and clonal longevity is also similar in these clones. DNA damage levels are reduced by culture in 5% oxygen, but longevity is not improved. This may be because of the requirement for intermittent reactivation via receptor pathways dependent on free radical production in T cells. These recent findings from our international immunosenescence research consortium suggest that strategies other than telomere maintenance, better protection against free radicals, or improved DNA repair will be required for functional longevity extension of human TCCs. To obtain sufficient cells for adoptive immunotherapy of cancer, alternative avenues need exploration; currently, these include enforced expression of certain heat shock proteins and proteasome components, and interference with the expression of negative regulatory receptors expressed by T cells.

Antigens↗
PubMed2003

Insulin receptor and ageing.

The number of elderly people is increasing worldwide as well as the age-associated diseases, such as the type 2 diabetes. The consequences are disastrous for elderly patients as well as for healthy ageing. It has been clinically demonstrated that with physiological ageing it exists already a resistance to the action of insulin leading to slightly increased glycemia and insulin levels. Several causes have been postulated for this insulin resistance with ageing, among them the alteration of insulin receptor (IR) number, of IR signal transduction as well as environmental changes. Much more studies are needed to understand correctly the age-related changes of IRs mainly in humans. In this review, we will summarize our actual knowledge in the context of ageing on IRs trying to include it in a more general picture of receptor physiology with ageing. The understanding of the IR physiology with ageing will help to develop more adequate preventive and therapeutic strategies in order to decrease the burden of the complications related to insulin resistance.

Aging↗