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PubMed1996

Salt effects on peptide conformers: a dielectric study of tuftsin.

Four 1-ns molecular dynamics computer simulations of tuftsin, Thr-Lys-Pro-Arg, are analyzed: (1) cis tuftsin in water, (2) trans tuftsin in water, (3) cis tuftsin in 1 M NaCl, and (4) trans tuftsin in 1 M NaCl. Independently of the salt concentration, the trans conformer has a higher dielectric constant than the cis conformer because the former exhibits a more widely distributed charge distribution in space. Independently of the peptide conformation, the presence of salt reduces the dielectric constants of both the peptide and the solvating water molecules because ions, on binding, restrict the motion of other atoms. In contrast to the dielectric constants, neither the peptide conformation nor the salt concentration shows a significant influence on the dielectric relaxation time of water molecules.

Electrochemistry↗

PubMed1997

ADP-ribosylation of tuftsin suppresses its receptor-binding capacity and phagocytosis-stimulating activity to murine peritoneal macrophages.

Arginine-specific ADP-ribosyltransferase present in granules of chicken polymorphonuclear leukocytes (so-called heterophils) is released into the extracellular space by stimulus of calcium ionophore A23187 or opsonized zymosan [Terashima et al. (1996) J. Biochem. 120, 1209-1215]. In the present work, we examined extracellular targets of the released transferase and identified tuftsin, a phagocytosis-stimulating tetrapeptide derived from leukokinin, as a preferential substrate of the enzyme in chicken plasma. Specific binding of FITC-tuftsin to murine peritoneal macrophages, observed under a fluorescent microscope, was impaired by ADP-ribosylation of the labelled peptide. Phagocytic assay analyzed by flow cytometry revealed that ADP-ribosylation of tuftsin decreased its phagocytosis-stimulating activity towards the macrophages. Thus, the ADP-ribosylation of tuftsin apparently decreases its biological activity and ADP-ribosylation may possibly be involved in inflammatory processes through alterations in tuftsin activity.

Adenosine Diphosphate Ribose↗

PubMed2005

Immunomodulator tuftsin increases the susceptibility of Cryptococcus neoformans to liposomal amphotericin B in immunocompetent BALB/c mice.

The co-administration of immunomodulators and antibiotics has been proved very successful for treatment of opportunistic infectious diseases. In the present study, we evaluated the combination of liposomal amphotericin B (lip-Amp B) and immunomodulator tuftsin to cure Cryptococcus neoformans infection in BALB/c mice. Mice infected with C. neoformans were treated with Amp B deoxycholate and tuftsin free or tuftsin-loaded Amp B liposomes. The results of the present study demonstrated higher efficacy of tuftsin-loaded Amp B liposomes against experimental murine cryptococcosis, in terms of enhanced survival rate and reduced fungal burden in organs (lungs and brain) of the treated mice. Interestingly, pre-treatment of mice with liposomal tuftsin before challenging them with the C. neoformans infection resulted in 100% survival of the treated animals followed by treatment with lip-Amp B. Immunomodulator-based therapy seems likely to be more beneficial for treatment of fungal infectious diseases.

Amphotericin B↗

PubMed1986

Suppression of Friend virus-induced leukaemia in mice by tuftsin.

A significant decrease in mortality was observed when 25 micrograms of the tetrapeptide tuftsin was given to DBA/2J mice 5 days before infection with Friend leukaemia virus (FLV). The same effect was observed when tuftsin was given 5 days before and twice a week for 3 weeks after FLV infection. No effect was observed when the same amount of tuftsin was given 1 day before infection. A 5 micrograms dose of tuftsin given 5 days before and twice-weekly for 3 weeks had no effect on leukaemia induced by FLV infection. These findings showed that time and dosage were critical to the protective effect of tuftsin against virus-induced leukaemia.

Animals↗

PubMed1977

Decreased tuftsin concentrations in patients who have undergone splenectomy.

Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin's disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin's disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin's disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin's disease should perhaps be reconsidered.

Adult↗

PubMed1998

Impaired splenic function and tuftsin deficiency in patients with intestinal failure on long term intravenous nutrition.

BACKGROUND: Reticuloendothelial system function is impaired in humans receiving lipid regimens. AIMS: To evaluate the effects of long term administration of long chain triglyceride emulsions on reticuloendothelial system function. METHODS: Splenic function and tuftsin activity were measured in 20 patients on intravenous nutrition for intestinal failure, 20 patients with Crohn's disease who were not receiving intravenous nutrition, and 50 healthy controls. RESULTS: Pitted red cells counts in patients on intravenous nutrition (8.0%) were significantly higher (p<0.001) than in healthy controls (0.6%) and in patients with Crohn's disease (0.9%). No difference was found between healthy controls and patients with Crohn's disease. There was a correlation (r=0.50; p<0.03) between percentage of pitted red cells and duration of intravenous nutrition. Tuftsin activity was significantly reduced in the intravenous nutrition patient group (6%) compared with both disease controls (16.5%, p<0.01) and healthy volunteers (17.8%, p<0.001). An inverse correlation between tuftsin activity and pitted red cell percentage was found in the patients on intravenous nutrition (r(s) =-0.44, p<0.05). No relation was found in the patients on intravenous nutrition between pitted red cell percentage or tuftsin activity and type of disease, percentage of ideal body weight, residual length of small intestine, or administration (quantity and frequency) of lipid emulsion. Eight patients on intravenous nutrition had serious infections within the previous 12 months. CONCLUSIONS: Patients with a short bowel treated with long term intravenous nutrition have impaired splenic function, reduced tuftsin activity, and an increased risk of infection.

Adult↗

PubMed1989

Tuftsin: its chemistry, biology, and clinical potential.

Tuftsin is a tetrapeptide, Thr-Lys-Pro-Arg, which resides in the Fc-domain of the heavy chain of immunoglobulin G. The peptide originates from a specific fraction of the parent protein through enzymatic processing. Tuftsin possesses a broad spectrum of activities related primarily to the immune system function and exerts on phagocytic cells, notably on macrophages. These include potentiation of various cell functions such as phagocytosis, motility, immunogenic response, and bactericidal and tumoricidal activities. The features of tuftsin, coupled with its low toxicity, make the peptide an attractive candidate for immunotherapy. Tuftsin's capacity to augment cellular activation is mediated by specific receptors that were identified, characterized, and recently isolated from rabbit peritoneal granulocytes. Tuftsin has been chemically synthesized by a variety of techniques, some of which are adequate for large-scale preparations. A multitude of analogs have also been synthesized and extensively studied for structure-function relationships.

Adult↗

PubMed1993

Modulation of peripheral blood derived monocytes/macrophages from leprosy patients using 'tuftsin' for production of reactive oxygen intermediates.

Phagocytic cells respond to a variety of membrane stimulants by producing reactive oxygen intermediates (ROI), i.e. O2-, H2O2 and OH.metabolites. Plasma membrane activation is associated with superoxide generating NADPH oxidase, thereby causing the production of these toxic species. Stimulation of phagocytic cells also results in activation of purine catabolism, which directs the metabolic flux through xanthine oxidase to produce the superoxide anion. We previously observed that BL/LL macrophages (M phi) exhibited a premature inability to undergo tuftsin stimulated phagocytosis and microbicidal activity. The present study was undertaken to measure ROI levels in the absence and presence of 'tuftsin' pulsing as a function of in vitro culture age and also correlated these levels with adenosine deaminase (ADA) activity. The latter is known to be a contributor of O2- generation and is also involved in the maturation of the monocyte/macrophage system. The behaviour of normal and tuberculoid monocytes/macrophages were more or less the same, either in the presence or absence of tuftsin, i.e. they showed a progressive increase in ROI production until day 3, then tapered off in older cultures by day 7. In contrast, after day 1, the lepromatous macrophages were unable to undergo tuftsin mediated stimulation for the production of ROI and ADA activity. These findings indicate a defective M phi function in lepromatous patients towards tuftsin pulsing, thereby supporting our earlier observations. Thus BL/LL M phi behaved as if they were aged after 1 day of in vitro culture, which may account for an inability to handle Mycobacterium leprae for efficient killing.

Adenosine Deaminase↗

PubMed1992

[Prolonged action of tuftsin in penicillin epilepsy].

The free behaviour experiments on rats showed during the first day the tuftsin-induced (0.3 mg/kg i. p.) increment of epileptic discharge in all the structures simultaneously. Open field behaviour depended on the sequence of penicillin and tuftsin injections. The rats with tuftsin used after the epileptiformic activity has been developed showed the behaviour analogical to the penicillin-injected animals. The preventive injections of tuftsin resulted in restoration of all behavioural indications by the third day. The optimal corrective effect has been obtained with tuftsin used preventively.

Animals↗

PubMed1988

Antigen-tuftsin conjugate signals interleukin-1 synthesis and secretion.

The immunoglobulin heavy chain derived tetrapeptide, tuftsin (Thr-Lys-Pro-Arg), known for its phagocytosis-stimulating activity, was found to augment the antigen-presenting capacity of macrophages in culture, when applied simultaneously with antigen. Injection of antigens or antigens admixed with tuftsin had no immunogenic effect in vivo. On the other hand, antigen-tuftsin covalent conjugates, injected in aqueous solution intramuscularly or intravenously, significantly augmented antibody production. Studying the mechanism underlying these immunogenic effects, we demonstrate that tuftsin, when applied to macrophages together with, or conjugated to, antigens, signals de novo synthesis of mRNA encoding for interleukin-1 (IL-1), and induces secretion of IL-1 from the cells. We suggest that triggering the immunogenic processes by tuftsin conjugates is a consequence of up-regulation of IL-1 synthesis and secretion.

Animals↗

PubMed2005

Synthesis and biological activity of tuftsin, its analogue and conjugates containing muramyl dipeptides or nor-muramyl dipeptides.

Several conjugates of muramyl dipeptide (MDP) or nor-muramyl dipeptide (nor-MDP) with tuftsin were synthesized. Conjugates 8a-f were prepared by acylation of protected tuftsin with the isoglutamine carboxyl group of MDP or nor-MDP 2a-f. Also tuftsin analogue 6 (H-Thr-Lys-Pro-Arg(NO2)-OH) was obtained. All synthesized compounds were investigated at the Medical University of Gdansk. The biological activity of the examined compounds was estimated using in vitro cultures of human monocytes and lymphocytes. The substances displayed cytotoxic effects, as was revealed in the viability tests performed. The effects were most probably mediated by the induction of an oxidative burst in monocytes and the stimulation of redox enzymes in lymphocytes. In addition, the analogues turned out to be efficient stimulators of TNFalpha and IL6 secretion by monocytes and lymphocytes. Nevertheless, the secretion of cytokines did not affect the viability of the leukocyte population used in the experiments.The beneficial properties of the compounds examined (mainly 6, 3, 8a and 8c), which implies their usefulness as potential therapeutic agents, are connected with their rapid start of action and more efficient effects compared with tuftsin alone. An in vivo assay on animal models will be performed.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1980

Functional tuftsin binding sites on macrophage-like tumor line P388D1 and on bone marrow cells differentiated in vitro into mononuclear phagocytes.

Mouse bone marrow cells, differentiated in vitro into mononuclear phagocytes (BMDMP), posess functional tuftsin binding sites, i.e. both tuftsin binding capacity and augmented phagocytic response related to tuftsin binding. The binding capacity of BMDMP was shown to be higher by a factor of about three than that exhibited by mouse monocytes and by normal, thioglycollate and Corynebacterium parvum induced peritoneal macrophages. The relatively high binding capacity did not depend on experimental variations in the in vitro culture of these populations (i.e. length of in vitro cultivation, source of serum or presence of conditioned medium leading to cell proliferation). The macrophage-like line, P388D1, was also shown to possess functional tuftsin binding sites and its binding capacity was comparable to that of the peritoneal macrophage populations.

Animals↗

PubMed1980

The phagocytosis stimulating peptide tuftsin: further look into structure-function relationships.

Sixteen new analogs of the phagocytosis-stimulating peptide tuftsin have been synthesized. The biological activities of these synthetic peptides, in which either the C-terminal or both C- and N-terminals are chemically altered, were evaluated by studying their effects on the phagocytosis of heat-killed yeasts and on the reduction of the dye nitroblue tetrazolium by normal human polymorphonuclear leukocytes. The results demonstrate that the integrity of the guanidine side chain of arginine at position four of tuftsin is crucial for maximal activity. Modification, even in side chain length, of the guanidine leads to decreasing activity. Preservation of the positive charge of position four of tuftsin yields analogs possessing considerable activity. Simultaneous alterations of both C- and N-terminal results in diminishing activities. The results of this study are discussed in relation to the structural features of tuftsin. It appears that interaction between the carboxyl of Arg4 and the amino group of Thr1 which would indicate a specific conformation such as a 4 leads to 1 beta-turn are not favored.

Arginine↗

PubMed1982

Does tuftsin alter phagocytosis by human polymorphonuclear neutrophils?

The physiological significance of the putative phagocytosis-promoting peptide, tuftsin, was investigated by measurement of chemiluminescence generated during phagocytosis and by assay of the uptake of radiolabeled bacteria. We found no differences in either assay when we compared serum from splenectomized patients (which purportedly lacks tuftsin) with normal serum. Further, there was no difference when serum from splenectomized patients was employed in the presence of absence of exogenous tuftsin. Similar results were obtained under a variety of conditions, utilizing three different challenge particles with varying particle-cell ratios and serum from 20 different splenectomized patients. These results do not agree with the hypothesis that tuftsin plays a major role in promoting phagocytosis.

Blood↗

PubMed1979

The clinical and physiological aspects of tuftsin deficiency syndromes exhibiting defective phagocytosis.

The tetrapeptide tuftsin (Thr-Lys-Pro-Arg) stimulates phagocytosis by blood neutrophilic granulocytes and tissue macrophages in a highly specific manner. Tuftsin is cleaved off the carrier gamma-globulin molecule as the free active form by two enzymes. One of these is in the spleen and the other on the outer membrane of the phagocyte. Congenital tuftsin deficiency usually arises when the peptide is mutated to an inactive peptide. The acquired type occurs if the spleen function is curtailed by removal or disease. Tuftsin deficiency is manifested by severe recurrent infections involving primarily the skin, lymph nodes and lungs. Therapy is limited to gamma-globulin injection along with appropriate chemotherapy.

Dysgammaglobulinemia↗

PubMed1992

Respiratory burst in peritoneal exudate cells in response to a modified tuftsin.

Intraperitoneal administration of tuftsin-M [Thr-Lys-Pro-Arg-NH-(CH2)2-NH-CO-C15H31] to Balb/C mice has been shown to induce a respiratory burst in the peritoneal exudate cells. The macrophages exhibited enhanced levels of O2-, H2O2, NADPH oxidase and myeloperoxidase, but the activities of superoxide dismutase, catalase and glutathione peroxidase remained virtually unchanged. The magnitude of the oxidative burst depended directly on the dose of tuftsin-M; higher activity was observed at higher doses of the peptide. Tuftsin-M enhanced the generation of both O2- and H2O2 under in vitro conditions, as did phorbol myristate acetate. These results suggest that tuftsin-M could enhance non-specific defence against infections by activating the macrophages.

Analysis of Variance↗

PubMed1997

Morphochemical changes in brain structures in the course of chronic haloperidol treatment and the correction of these changes with tuftsin.

The systemic injection of haloperidol (4 wk, 0.5 mg/kg/d) caused the increase of protein concentration and content, and the activity level of aminopeptidase in the cytoplasm of the neurons of associated type (layer III). The nucleus of these cells decreased both in sizes and in the content of proteins. In the neurons of efferent-projectory type (layer V), the decrease of studied peculiarities as compared with control level was observed. Tuftsin (300 micrograms/kg/d) injection after chronic haloperidol treatment causes the restoring action on changed parameters in sensomotor cortex. In caudate nucleus, tuftsin influence caused further reduction of neuron's cytoplasmic area and significant reduction in protein content. The received results testify to the morphobiochemical heterogenity of investigated brain structures, which is displayed both in the case of haloperidol treatment and in the case of its correction by neuropeptide tuftsin. Chronic haloperidol administration to animals can develop a model of certain symptoms and syndromes of parkinsonism. Its most pronounced manifestation is an imbalance in the neuromediator systems, especially the dopaminergic one (Mettler and Crandall, 1959; Colls, 1984; Funk et al., 1986). The research was performed in conjunction with the physiologists, whose experiments have shown that after chronic haloperidol administration, changes in animal behavior are developed that are typical for bradikinesia, and the motor regimen of integration is disturbed (Popova and Kachalova, 1991; Dovedova and Povova, 1993). Regulatory drugs, especially the tetrapeptide tuftsin, seem to correct such disturbances.

Aminopeptidases↗

PubMed1987

The identification of serum tuftsin by reverse-phase high-performance liquid chromatography and mass spectrometry.

We describe for the first time a method for unambiguously identifying the phagocytic stimulating tetrapeptide tuftsin from trypsinized human serum. The method consists of separating serum tuftsin by reverse-phase (RP)-HPLC, collecting HPLC fractions corresponding to the synthetic tuftsin retention time, and then subjecting those fractions to mass spectrometry/mass spectrometry (MS/MS) analysis, which provides optimal molecular specificity to the measurement. Although quantification was not the goal, it was estimated that the amount of tuftsin found by RP-HPLC and MS/MS was in the hundreds of nanograms per milliliter.

Chromatography, High Pressure Liquid↗