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PubMed1990

Tuftsin increases survival in murine peritoneal carcinomatosis.

Tuftsin increases macrophage superoxide anion generation as well as chemotactic, phagocytic, and secretory activities. The antitumor effect of tuftsin is mediated through the increased cytotoxic properties of primed macrophages. Peritoneal carcinomatosis presents a tumor model where the antineoplastic activation of peritoneal macrophages can be studied. Tuftsin given by intraperitoneal injection into Balb/C mice with peritoneal carcinomatosis demonstrated significant improvement in survival rates of treated mice over controls. Superoxide generation by peritoneal macrophages was increased by tuftsin; however, after progressive tumor growth, there was a reduction in the amount of superoxide produced. In the group treated with carrageenan, the survival rate was lower than in controls. The superoxide generation was increased by carrageenan, but to lower levels than by tuftsin. The assay of superoxide generation by macrophages by itself cannot be used as a measure of tumor cytotoxicity induced by tuftsin.

Animals↗
PubMed1990

Tuftsin induces tissue factor-like activity in human mononuclear cells and in monocytic cell lines.

Normal human monocytes and macrophages generate potent procoagulant activity (PCA) resembling tissue factor (TF) in response to various stimuli. In this study we show that tuftsin, a natural stimulator of many functions of monocytes and macrophages, also stimulates a potent PCA in mixed mononuclear cells and monocytes, and a mild PCA in lymphocytes and cell lines of monocytic origin (U937 and THP). No activity was generated by several lymphoid cell lines and HL-60 cells. The PCA resembled TF in that it accelerated clotting through the extrinsic coagulation pathway and was inhibited by concanavalin-A and by monoclonal anti-TF antibodies. The induction of TF-like activity by tuftsin was dose- and time-dependent. It was located in the cell membrane and did not require T cells for expression. Generation of TF-like activity was prevented by actinomycin D, while cytarabine had no effect on this process, suggesting that expression of the activity depends on protein synthesis. Studies with various tuftsin analogs suggest that tuftsin stimulates generation of TF-like activity, as well as other functions of monocytes via the same receptors. The results with the monocytic cell lines show that tuftsin affects mainly mature cells. The induction of TF-like activity in mononuclear cells by tuftsin constitutes an important link between mononuclear cells and the immune and coagulation systems. It may play a major role in the pathogenesis of thromboembolism and fibrin deposition in various inflammatory and immunologic disorders.

Blood Coagulation Factors↗
PubMed1989

Tuftsin stimulates IL-1 production by human mononuclear cells, human spleen cells and mouse spleen cells in vitro.

Human peripheral adherent cells from splenectomized subjects, human spleen cells and mouse spleen cells were tested for IL-1 production in vitro in presence or absence of synthetic tuftsin (Thr-Lys-Pro-Arg). Application of synthetic tuftsin to peripheral blood adherent cells from normal donors as well as from splenectomized subjects induces IL-1 production. In splenectomized subjects the extent of induction was more evident than in controls. In human splenic cells tuftsin stimulates IL-1 production without KLH or LPS. In mouse spleen cells tuftsin alone did not stimulate the IL-1 secretion. However, addition of tuftsin to mouse spleen cells incubated with KLH augmented significantly the IL-1 secretion. As removal of the spleen leads to tuftsin deficiency, our present findings may perhaps explain the fulminant nature of the postplenectomy sepsis and some immune disturbances described in the postplenectomy state.

Animals↗
PubMed1987

Do tuftsin and bestatin constitute a biopharmacological immunoregulatory system?

Tuftsin is the tetrapeptide Thr-Lys-Pro-Arg. It is spontaneously released from the Fc fragment of IgG by two specific enzymes. One 25-micrograms dose administered to mice in good immunologic status stimulated phagocytosis, macrophage killing of tumor cells, delayed hypersensitivity, cytolytic T-cell activity, antibody production, antibody-dependent cell-mediated cytotoxicity (ADCC), and natural killer (NK) cell activity. Administered for 6 months at the dose of 10 micrograms once a week to old, immunodepressed mice, tuftsin restored macrophage and T-cell cytotoxic activities. At this dosage, tuftsin prevented spontaneous tumor development. Tuftsin was also well tolerated in phase I studies in humans in increased polymorphonuclear leukocytes and OKT4-positive lymphocytes. Bestatin is extracted from Streptomyces olivoreticuli. One 100-micrograms dose of bestatin injected in young mice with normal immunologic status increased macrophage cytotoxicity, antibody production, ADCC, and NK cell activities. Long-term administration of bestatin (100 micrograms once a week) corrected macrophage and T-cell cytotoxicity and prevented age-related spontaneous tumors. Bestatin inhibited lymphocyte membrane aminopeptidase, which degrades tuftsin into a tripeptide that is an antagonist competing with it for receptors. Tuftsin and bestatin constitute a biopharmacologic system that can be developed as other aminopeptidase inhibitors are available for study.

Adjuvants, Immunologic↗
PubMed1988

[Effect of the immunostimulator tuftsin on the heart rate and body temperature of albino rats].

Tetrapeptide tuftsin (0.3 mg/kg) affected the heart rate and body temperature depending on basal physiological parameters: when administered in the state of low heart rate tuftsin produced positive chronotropic effect, whereas at higher basal heart rate the bradycardiac response was observed. Tuftsin caused biphasic changes of the body temperature: transient hyperthermia in 5 min. after peptide injection with subsequent longer period of hypothermia followed by restoration of basal level. No effect of tuftsin occurred after reserpine injection. At the same time tuftsin potentiated the hypothermia induced by reserpine. The time course and sign of vegetative effects of tuftsin correlate with some of its behavioural effects.

Animals↗
PubMed1985

Effects of tuftsin on postsplenectomy sepsis.

Tuftsin is a tetrapeptide within the CH2 domain of the IgG immunoglobulin. Enzymatically cleaved from its parent globulin, it increases the phagocytic activity of macrophages, monocytes, and neutrophils by specific receptor mechanisms. In splenectomized hosts the circulating levels of tuftsin are reduced. Postsplenectomy sepsis is due to impaired clearance of intravascular bacteria; it has been postulated that tuftsin deficiency may contribute to this impairment. In this experiment splenectomized DBA/2 mice were subjected to pneumococcal sepsis. The groups of mice treated with tuftsin and those that received autotransplanted splenic tissue had significantly improved survival rates. We conclude that tuftsin deficiency plays a role in postsplenectomy sepsis and that treatment with synthetic tuftsin protects the splenectomized host against pneumococcal septic death.

Animals↗
PubMed1982

[Analysis of the neurochemical mechanisms of the psychotropic action of tuftsin and its analogs].

A study was made of the central effects of tuftsin (Thr-Lys-Pro-Arg) and its analogs (Leu1-tuftsin, D-Arg4-tuftsin) on the dopamine-dependent behavior and tyrosine hydroxylase (TH) activity. It was shown that the absence of direct effect of tuftsin and Leu1-tuftsin on postsynaptic dopaminergic receptors, revealed in experimental rotational behavior, correlates with a decrease in TH activity in the rat hypothalamus and striatum. Depression of the rotational behavior and increased activity of TH under the effect of D-Arg4-tuftsin suggest that this analog can modulate postsynaptic dopaminergic receptors by the antagonism type.

Animals↗
PubMed1981

Biochemical aspects of tuftsin deficiency syndrome.

From work reported so far it is possible to draw certain conclusions namely, that Tuftsin, Thr-Lys-Pro-Arg, is a biologically functional entity. The presence of congenital familial deficiency reinforces this conclusion. The fact that these patients suffer from repeated infections points at an in vivo system that parallels the in vitro studies showing tuftsin stimulation of the phagocytic activity of the tissue macrophage and blood granulocyte. Such stimulation occurs at hormonal concentrations; (half maximal at 100 M). Furthermore, tuftsin enchances pinocytosis, as it does phagocytosis, only in phagocytic cells. It stimulates the motility of these cells as well as their longevity. Tuftsin stimulates the hexosemonophosphate shunt and, presumably through the formation of active oxygen-derived compounds, augments the bactericidal as well as the tumoricidal activity of the macrophage. There are highly specific receptors on the cell membrane of phagocytic cells. The structure of tuftsin cannot be altered without producing inactive and/or inhibitory analogs, an exception being the interchange of lysine and arginine. The release of tuftsin from carrier leukokinin requires two enzymes, one of which is on the outer membrane of the phagocyte and the other in the spleen. The absence of the latter explains the deficiency observed after the abrogation of splenic function for whatever cause.

Animals↗
PubMed1982

[Comparative study of the psychotropic activity of tuftsin and its analogs].

Tuftsin and its Leu1 and D-Arg4 analogs displayed stimulating activity in experimental behavioral despair in mice. In rats with different types of emotional reactions and with destroyed catecholamine terminals (6-OHDA treatment), tuftsin increased exploratory activity, with fear manifestations being decreased and avoidance behavior improved. This was shown while testing the rats in the "open field" and according to the ability to accomplish an extrapolation task of avoiding critical stress-situation. Leu1-tuftsin increased the emotional stress and sharply hindered the avoidance reaction, while D-Arg4-tuftsin modulated the behavior of the animals with increased emotional reactivity and made the avoidance behavior prompter. Pentapeptide, an inhibitor of tuftsin stimulation of phagocytosis, had no significant effect on the behavior. Modifications in the structure of tuftsin resulted both in the changes in phagocytosis-stimulating activity and the appearance of other psychotropic effects.

Animals↗
PubMed2005

Tuftsin-AZT conjugate: potential macrophage targeting for AIDS therapy.

The IgG-derived immunomodulating peptide tuftsin, Thr-Lys-Pro-Arg, is recognized by specific receptors on phagocytic cells, notably macrophages, and is capable of targeting proteins and peptides to these sites. Aiming to target 3'-azido-3'-deoxythymidine (AZT) to HIV-infected macrophages, a conjugate of AZT with tuftsin was synthesized. The AZT-tuftsin chimera possesses the characteristic capacities of its two components. Thus, like AZT, it inhibits reverse transcriptase activity and HIV-antigen expression, and similarly to tuftsin, it stimulates IL-1 release from mouse macrophages and augments the immunogenic function of the cells. Importantly, the conjugate is not cytotoxic to T-cells. The results suggest that the AZT-tuftsin conjugate might have potential use in AIDS therapy.

Animals↗
PubMed1981

Antitumor effect of tuftsin.

Tuftsin, a physiological tetrapeptide derived from the Fc region of leukophilic IgG possesses a variety of immunopotentiating properties including the ability to act as an immunotherapeutic agent against the experimental tumors, L1210 leukemia and Cloudman S-91 melanoma. Although the mechanism of action of tuftsin in vivo is not known, several types of leukocytes have been shown to become cytotoxic effector cells following activation with tuftsin. These cells presently include macrophages, natural killer cells, and granulocytes. The possibility that tuftsin can also activate other types of effector cells have not been ruled out. We feel this small peptide has a high potential (largely unrecognized) as an antitumor immunopotentiating agent. It is naturally occurring in man and appears to be relatively non-toxic. Its exact sequence (Thr-lys-Pro-Arg) is known and it can be chemically synthesized. Methods are also available to monitor the levels of tuftsin in body fluids. These properties along with its ability to control infectious disease make this agent one of the more promising immunopotentiators.

Animals↗
PubMed1981

Bactericidal activity of tuftsin.

The biological activities of the phagocytosis stimulating tetrapeptide, Thr-Lys-Pro-Arg are discussed. A brief account on the stimulation by tuftsin of phagocytosis of various particles, including bacteria was reported. Stimulation of bactericidal activity by this tetrapeptide was investigated in vitro as well as in vivo. The potency of tuftsin to enhance blood clearing of Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Serratia marcescens by mouse peritoneal macrophages was demonstrated. Bactericidal activity and effects of tuftsin on this phenomenon were studied in liver and spleen of mice. Tuftsin stimulates these activities. Same experiments were performed in infected leukemic mice by Serratia marcescens or Escherichia coli. Results on blood clearing and bactericidal activities in liver and spleen were reported and compared to those of healthy and leukemic untreated animals. Tuftsin was found to present interesting stimulatory effects on the bactericidal activity of phagocytes.

Animals↗
PubMed1980

On the mechanism of action of the phagocytosis-stimulating peptide tuftsin.

Incubation of human polymorphonuclear leukocytes (PMNL) or thioglycollate-stimulated mouse peritoneal macrophages with the phagocytosis-stimulating peptide, tuftsin (2.5 X 10(-7) M, at 37 degrees C), caused an increase of 80-90% in intracellular cGMP levels, accompanied by a decrease of 20-25% in intracellular cAMP levels. Significant changes in cyclic nucleotide levels were detectable after 4 min of incubation, were maximal at 10-20 min and persisted for at least 60 min. The concentration dependences of the stimulatory effect of tuftsin on modulation on intracellular levels of cyclic nucleotides and on phagocytosis are similar, suggesting a cause and effect relationship between the two phenomena. This notion is further supported by the finding that 8-Br-cGMP and 8-Br-cAMP elicit stimulatory and inhibitory effects on macrophage phagocytosis, respectively. Measurement of 45Ca2+ influx into PMNL and macrophages in the presence and absence of tuftsin did not reveal any change in 45Ca2+ uptake from the media. However, tuftsin did enhance release of 45Ca2+ from cells preloaded with the isotope. Results suggest that modulation of both the amount of cell-associated 45Ca2+ and the intracellular levels of cyclic nucleotides are key steps in the mechanism by which tuftsin augments phagocytosis.

Animals↗
PubMed1991

Tuftsin deficiency in AIDS.

Tuftsin is an endogenous tetrapeptide that stimulates phagocytosis and is released from the Fc fragment of IgG by a splenic endocarboxypeptidase. Tuftsin activity and splenic function were measured in 21 patients with AIDS, 7 patients with AIDS-related complex (ARC), 22 patients who had undergone splenectomy, and 37 healthy volunteers. There was a significant inverse correlation between tuftsin activity and splenic function in all subjects. Tuftsin activity was significantly lower in patients with AIDS, ARC, and in those who had undergone splenectomy compared with healthy volunteers. Tuftsin deficiency may contribute to the risk of bacterial infection in symptomatic HIV-positive individuals.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

In vivo immunopharmacological properties of tuftsin and four analogs.

Four analogs of the natural macrophage-activator peptide tuftsin (T-K-P-R) were synthesized with the aim of obtaining compounds more effective in the stimulation of the immune system than tuftsin. Modifications to the parent tuftsin molecule were (i) substitution of the proline (P) residue, and/or (ii) replacement of the N-terminal residue threonine (T). The study presented here shows that the integrity of the NH2 terminus is not mandatory for a full biological tuftsin-like activity. Our data also suggest that the analogue F-(psi)-K-ABO-R, where ABO is a non-natural amino acid, is a promising agent for immunotherapy of infectious and neoplasic diseases for which tuftsin has already demonstrated some efficacy.

Amino Acid Sequence↗
PubMed1983

Tuftsin stimulates the release of oxygen radicals and thromboxane from macrophages.

The physiologically occurring tetrapeptide, tuftsin (Thr-Lys-Pro-Arg), was examined for its effects on guinea pig peritoneal macrophages. Adherent macrophages (møo) were exposed to tuftsin at concentrations ranging from 10(8) to 10(6) M, and the release of oxygen radicals and the arachidonic acid cyclo-oxygenation product, thromboxane B2 (TXB2), was studied. Tuftsin causes both albumin-elicited and C. parvum-activated møo to set free superoxide anion (O2) and hydrogen peroxide (H2O2). It also stimulates the liberation of TXB2 from albumin-elicited møo. The demonstrated induction of the release of toxic oxygen species from møo by tuftsin may explain how tuftsin-augmented møo-mediated cytotoxicity is accomplished.

Animals↗
PubMed1991

Priming of normal human neutrophils by tachykinins: tuftsin-like inhibition of in vitro chemotaxis stimulated by formylpeptide or interleukin-8.

Tachykinins have priming effects on polymorphonuclear neutrophils, since they may activate the neutrophils to exhibit an exaggerated inflammatory response to phlogistic mediators. In order to investigate mechanisms involved in this action, we determined the influence of substance P and neurokinin A on chemotaxis of human neutrophils towards gradients of formymethionyl-leucyl-phenylalanine or recombinant human interleukin-8. As seen with other neutrophil-priming agents such as tumor necrosis factor-alpha, exposure of neutrophils to substance P or neurokinin A had an inhibitory effect upon a stimulated migration, with effective concentrations being in the nanomolar range. Tuftsin, a known neutrophil activating peptide, similarly inhibited stimulated migration. Analysis of structure-activity relationships revealed that activity of tachykinins is located in amino-terminal, tuftsin-like sequences. The inhibition of stimulated migration was partly reversed by (Pro1)-tuftsin, a partial tuftsin receptor antagonist, which suggests that the effects of amino-terminal tachykinins involves activation of tuftsin receptors of neutrophils.

Amino Acid Sequence↗
PubMed1990

Modulation of human lepromatous monocyte-macrophage functions in vitro by tuftsin.

Human peripheral blood monocytes/macrophages derived from normal donors, patients of tuberculoid leprosy (BT/TT) and lepromatous leprosy (BL/LL) were assayed for stimulated phagocytic responses to the potent macrophage stimulator "Tuftsin" (NH2-Thr-Lys-Pro-Arg-OH) after varying periods (6 h to 14 days) of culture in vitro. The assays consisted of visual scoring of ingested Mycobacterium leprae and radiometric measurement of ingested 14C-acetate labelled Staphylococcus aureus and Mycobacterium tuberculosis (H37Ra). While normal and BT/TT macrophages showed a progressively increasing ability for tuftsin-stimulated phagocytosis with increasing age of culture in vitro, BL/LL macrophages showed the opposite response so that 14-day cultures were refractory to a stimulatory dose of up to 7.0 microM (10 to 20 times the optimal dose for normal and BT/TT macrophages). The 14-day BL/LL macrophage cultures were, however, responsive to 35 microM tuftsin (100 times the optimal dose for normal macrophages). Analysis of the dose-response curves also indicates that BT/TT cultures despite exhibiting an apparent similarity to normal macrophages demonstrate a rightward shift for a maximal stimulated phagocytosis. Finally SEM photo-micrographs of 14-day macrophage cultures of the three groups revealed that while normal and BT/TT cultures demonstrated an increase in membrane ruffling and filopodia on stimulation with 0.8 microM tuftsin, BL/LL cultures exhibited none of the features associated with stimulation. From the above findings, we conclude that lepromatous macrophages may display an aberrant differentiation profile leading to a terminal state of unresponsiveness and that the defect may possibly lie at the level of tuftsin receptor expression or transmembrane signal transduction.

Amino Acid Sequence↗