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PubMed1982

Enhancement of phagocytosis by neurotensin, a newly found biological activity of the neuropeptide.

Specific binding of neurotensin (NT) to mouse peritoneal thioglycollate-elicited macrophages and macrophages differentiated in vitro from bone marrow cells was demonstrated and characterized. NT binding to these phagocytes modulated their phagocytic capacity in a biphasic manner. At concentrations of 10(-14) to 10(-9) M NT, a dose-dependent augmentation of phagocytosis (up to 2-fold) was observed. Further increases in the concentration of NT resulted in a gradual decrease of the augmented response until the basal phagocytic activity (in the absence of NT) was reached. Three partial sequences of NT, NT (8-13), NT (6-13) and NT (1-10), were also effective in augmenting the phagocytic response of thioglycollate elicited macrophages, but the maximal effect was attained at about 10(-7) M and stayed at that level up to a concentration of 10(-5) M. The activity of the three NT partial sequences was comparable to that of substance P and tuftsin. Scatchard analysis of (3H)NT binding to macrophages suggested the existence of two populations of binding sites, a major population of relatively low affinity binding sites and a small population of high affinity binding sites. NT (8-13), NT (6-13), substance P and tuftsin competed with (3H)NT binding to the low affinity sites with a comparable KI to that of NT. NT (1-10) did not compete for the binding at the low affinity sites. It is suggested that NT binding to the high affinity sites leads to enhancement of phagocytosis, whereas its binding to the low affinity sites leads to inhibition of the augmented response. However, the low affinity sites are the sites of interaction of NT (8-13), NT (6-13), substance P and tuftsin with the phagocytes and their saturation with the peptides leads to augmentation of phagocytosis.

Amino Acid Sequence↗
PubMed1998

Anti-IL-1 activity of peptide fragments of IL-1 family proteins.

A series of peptides containing retro-tuftsin- and tuftsin-like motifs from IL-1 proteins inhibits IL-1-induced IL-2 production and reduces the humoral immune response, thus supporting our hypothesis that tuftsin (Thr-Lys-Pro-Arg)-IL-1 competition depends on the presence of such motifs in IL-1 proteins. Some other peptides from regions of IL-1 responsible for receptor binding were also active, with peptide Ile-Thr-Gly-Ser-Glu (III) from IL-1alpha (residues 98-102), not only strongly affecting IL-2 production, but also suppressing the immune response; the analogue of hexapeptide Val-Thr-Lys-Phe-Tyr-Phe from the C-terminal part of IL-lra, with Lys replaced by Asp, was as efficient as Val-Thr-Lys-Phe-Tyr-Phe with respect to IL-1 competition.

Amino Acid Sequence↗
PubMed2001

Immunomodulatory potential of hydrophobic analogs of Rigin and their role in providing protection against Plasmodium berghei infection in mice.

Here, we report the immunomodulating potential of N-palmitoyl-amino-ethyl-rigin amide (PR) and N-cholestanyl-amino-ethyl-rigin amide (CR), the two new structural analogs of rigin (an IgG-derived tetrapeptide). Their activity profiles are compared with native tuftsin (NT) and/or N-palmitoyl-amino-ethyl-tuftsin amide (PT) taken as positive control. To explore the possibility of their use as targeting molecules, they are incorporated into the liposome bilayer and, subsequently, interacted with macrophages in an in vitro study. The new analogs of rigin with the hydrophobicity introduced at the C-terminus are found to considerably improve both the cell-mediated and the humoral immune responses in mice. However, unlike tuftsin and its analog, which mainly activate polymorphonuclear leukocytes and macrophages, the rigin analogs appear to manifest their response more through lymphocytes. When administered prophylactically to a group of mice, at the dose of 100 micrograms/0.5 ml/mouse/day for 2 days (i.v.), followed by a challenge presented with 1 x 10(6) rbcs parasitised with Plasmodium berghei on day 0, substantial reduction in parasitaemia and rate of mortality is observed. This led to increase the median survival time (MST) of the treated group in comparison to the control group. The response is found to be more prominent in CR-treated mice possibly because of the presence of steroid moiety, which is likely to have more productive interaction with cell membranes. Incorporation of these peptides into the bilayer of liposomes does not alter the permeability behavior of vesicles and, in fact, enhances their uptake by the macrophages in an in vitro study. The effect, however, is dependent on both, the concentration of peptide liposomes and the time of incubation. Present study, thus, establishes the possible use of these analogs not only as adjuvant in chemotherapy, but also as a prophylactic supplement to boost the natural immune status. The activity response of rigin analogs is manifested through lymphocytes, they can also find use in the chemotherapy of diseases, like leishmaniasis, tuberculosis and leprosy, where macrophage activity is either tamed or impaired by pathogens.

Adjuvants, Immunologic↗
PubMed2000

Polypeptide modification and cross-linking by oxidized 3-hydroxykynurenine.

3-Hydroxykynurenine (3OHKyn) is present in the mammalian lens as a UV filter and is formed from kynurenine in the tryptophan metabolic pathway. 3OHKyn is a readily autoxidized o-aminophenol which binds to proteins in vitro. The lens, particularly its central region, the nucleus, becomes increasingly oxidized with age. Under such conditions, the oxidation products of 3OHKyn may bind to lens proteins and contribute to nuclear cataract formation. The purpose of this study was to determine the structures of in vitro reaction products of 3OHKyn with model peptides as a general model for 3OHKyn modification of proteins. 3OHKyn was incubated with the dipeptide glycylglycine (GG) and the tetrapeptide tuftsin (sequence TKPR) under oxidizing conditions, and the reaction products were characterized by a variety of spectroscopic techniques. The major 3OHKyn-GG reaction product involves formation of a benzimidazole moiety between the GG N-terminus and the oxidized amino and/or phenol groups of 3OHKyn. In contrast, tuftsin, which has an N-terminal threonine, forms predominantly a cross-linked dimer with oxidized 3OHKyn. This product is analogous in structure to the dimeric reaction product, quinilinobenzoxamine, formed between oxidized 3OHKyn and glycyllysine [Aquilina, J. A., et al. (1999) Biochemistry 38, 11455-11464], which contains a benzoxazole moiety. The identification of a tuftsin dimer suggests that 3OHKyn can react with any peptide having a free alpha-amino group, via a general side chain elimination mechanism. The identification of both benzimidazole and benzoxazole adducts in peptides with a free N-terminus suggests that peptide amino groups can react initially at either the aromatic amino or hydroxyl group of oxidized 3OHKyn. The proportion of each adduct may change, however, depending on the amino acid sequence at the N-terminus.

Chromatography, High Pressure Liquid↗
PubMed1999

A reassessment of splenic hypofunction in celiac disease.

OBJECTIVES: Because there is controversy regarding the prevalence, familial occurrence, and possible factors inducing splenic hypofunction in celiac disease, we have reassessed them in a large series of untreated patients and their first-degree relatives. METHODS: Pitted red cell counting was used to measure splenic function and the effect that age at diagnosis has on it, while severity of intestinal lesions and nutritional status were estimated by multiple linear regression analysis. Moreover, serum tuftsin activity was assayed by measuring its ability to stimulate phagocytosis of opsonized Staphylococcus aureus. RESULTS: We found that 32.8% of untreated celiacs and none of their relatives had pitted red cell values in the range of splenic hypofunction (>4%). Only age at diagnosis, but not the other two covariates, was significantly associated with the degree of splenic hypofunction. Tuftsin activity was depressed in celiac disease and this reduction was significantly greater in hyposplenic patients. CONCLUSIONS: In celiac disease the prevalence of splenic hypofunction is lower than formerly believed. The duration of preexposure to gluten is a crucial factor for the prevalence and severity of this complication that does not affect celiac relatives. In celiac disease splenic hypofunction is accompanied by a reduced phagocyte activity linked to the decreased release of tuftsin.

Adult↗
PubMedDate not supplied

A hexapeptide VTKFYF from C-terminal part of interleukin-1 receptor antagonist, an inhibitor of IL-1-IL-1 receptor interaction.

In order to find the low-molecular-weight interleukin-1 (IL-1) inhibitors we synthesized a series of peptides, derived from three regions of interleukin-1 receptor antagonist (IL-1ra): N-terminal (residues 5-9), central (90-98) and C-terminal (143-148). The decision was based on the thorough analysis of structural and functional properties of IL-1 proteins and the resemblance of some fragments of IL-1ra to well-known immunomodulators, like thymopentin and tuftsin. The competition between our peptides and IL-1 was measured as the inhibition of IL-1 induced IL-2 production in LBRM/CTLL cell line system. The activity of tuftsin (TKPR), a peptide immunomodulator derived from IgG molecule, was also examined. All peptides presented some activity, although the most interesting results (when the range of activity and dose-dependence were taken into account) were obtained for tuftsin and peptide VTKFYF from the C-terminal part of IL-1ra, which is in agreement with the latest reports on the structure of IL-1ra-receptor complex.

Cell Line↗
PubMedDate not supplied

Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France.

This review discusses multivalency in the context of drug discovery, specifically the discovery of new diagnostic imaging and related agents. The aim is to draw attention to the powerful role that multivalency plays throughout research involving molecular biology, in general, and much of biochemically targeted contrast agent research, in particular. Two examples from the author's laboratory are described. We created small (approximately 5 kDa) peptide 'dimers' composed of two different, chemically linked peptides. The monomer peptides both bound to the same target protein with K(d) approximately 100 s nM, while the heterodimers had sub-nM K(d) values. Biological activity was evident in the heterodimers where none or very little existed in homodimers, monomers or monomer mixtures. Two different tyrosine kinases (KDR and C-Met) and four peptide families produced consistent results: multivalent heterodimers were uniquely different. The second example begins with making two micron ultrasound bubbles coated with the peptide, TKPPR (a Tuftsin antagonist) as a negative control for bubbles targeted with angiogenesis target-binding peptides. Unexpected binding of a 'negative' control, (TKPPR)-targeted bubble to endothelial cells expressing angiogenesis targets, led to the surprising result that TKPPR, only when multimerized, binds avidly, specifically and actively to neuropilin-1, a VEGF co-receptor. VEGF is the primary stimulator of angiogenesis. Tuftsin is a small peptide (TKPR) derived from IgG that binds to macrophages during inflammation, and has been studied for over 30 years. The receptor has never been cloned. The results led to new conclusions about Tuftsin, neuropilin-1 and the purpose, up to now unknown, of exon 8 in VEGF. Multivalency can be used rationally to solve practical problems in drug discovery. When targeting larger structures, multivalency is frequently unavoidable, and can lead to unpredictable and useful biochemical information, as well as to new drug candidates.

Biomarkers↗
PubMed1998

Extent and duration of recovered pupillary light reflex following retinal ganglion cell axon regeneration through peripheral nerve grafts directed to the pretectum in adult rats.

The functional reinnervation of the olivary pretectal nucleus (OPN) was studied in adult rats with peripheral nerve (PN) grafts bridging the interrupted retinopretectal pathway. Functional recovery was assessed quantitatively using established pupillometry techniques. The effect of intravitreal tuftsin fragment 1-3 (tuftsin 1-3) injections during the grafting procedure was also studied. A total of 53 adult rats received autologous PN grafts connecting the ocular stump of the transected optic nerve to the ipsilateral OPN. The contralateral eye was enucleated to remove the input from that eye to the OPN. A pupillary light reflex was elicited from 35 of the 53 PN-grafted animals and in the best cases, a response was obtained which compared closely to that recorded from control animals. Tuftsin 1-3 was found to increase the rate of recovery of the response. The response amplitude of PN-grafted rats was generally found to diminish with repeated stimulus presentation and also appeared to deteriorate with age. This was in contrast to control animals' responses. However, a PLR could still be elicited in 3 of the 6 animals studied 15 months after PN-grafting. These findings indicate that a near-normal PLR function can be restored using a peripheral nerve graft, but there are a number of factors that are likely to compromise optimal outcome.

Age Factors↗
PubMed2002

Microglial changes accompanying the promotion of retinal ganglion cell axonal regeneration into peripheral nerve grafts.

Intravitreal injection of the microglia inhibitor tuftsin 1-3 leads to an increase in retinal ganglion cell axonal regeneration into peripheral nerve grafts and a decrease in phagocytic cells in the retina. However, the relation of phagocytic cells and particularly microglia towards axonal regeneration remains unclear. Initially, to assess this, tuftsin 1-3's effect on axonal regeneration was reexamined by doing a dose-response study. Optimal doses were found to be 2.5 microg/ml and 250 microg/ml in rats and hamsters respectively. We then studied retinal phagocytic cells in rats. Microglial cells were classified as resting or activated based on their morphology following OX42 immunolabelling. In controls, most microglial cells were in the resting state. Optic nerve cut led to an increase in the total number of microglia and a ten-fold elevation in the proportion of activated cells; changes were more pronounced at the optic nerve stump. Anastomosis of an autologous segment of sciatic nerve to the stump of the freshly cut optic nerve minimized the overall increase in microglia, and combined with 2.5 microg/ml tuftsin 1-3, lead to a marked blunting of activation. Preservation within the retina of a higher proportion of resting over active form of microglia, and not the prevention of microglial proliferation per se, may be a crucial factor in allowing additional retinal ganglion cell axons to regenerate into peripheral nerve grafts.

Animals↗
PubMed1981

Prevention of spontaneous tumors of aged mice by immunopharmacologic manipulation: study of immune antitumor mechanisms.

Effects produced by long-term application of three immune modifiers (azimexon, retinoic acid, and tuftsin) on the depressed immune systems of 18-month-old inbred C57BL/6 female mice were investigated. The effect of each agent was examined on four cell types (cytotoxic T-cells, K-cells, NK cells, and macrophages) possibly involved in antitumor defenses and on the spontaneous tumor development that accompanied advancing age. Three substances chosen for this study appeared able to alter immune parameters, and each one displayed its own pattern of activity. Common to all three agents were an increase of age-depressed tumoricidal activity of peritoneal macrophages and no effect on the depressed NK activity of spleen cells. Retinoic acid increased splenic K-cell activity, already elevated in aged mice and unaffected by the other two agents. Cytotoxic T-cell activity, diminished by age, was stimulated considerably by retinoic acid and by tuftsin but only slightly by azimexon. Histopathologic studies revealed a decrease in the incidence of spontaneous tumors in the 3 treated groups. This decrease was statistically significant in the retinoic acid- and tuftsin-treated groups when compared with the incidence in untreated mice of the same age. Correlation of drug-induced modifications of the immune system with tumor incidence in aged mice was attempted.

Adjuvants, Immunologic↗
PubMed1983

Substrate specificity of aminopeptidase M: evidence that the commercial preparation is contaminated by dipeptidyl aminopeptidase IV and prolidase.

Commercial preparations of aminopeptidases M split Gly-Pro-beta-naphthylamide (Gly-Pro-2-NNap) into Gly-Pro and beta-naphthylamine, and Ala-Pro into Ala and Pro. The activities on Gly-Pro-2-NNap and Ala-Pro were completely inhibited by diisopropyl phosphorofluoridate (DFP) and p-chloromercuribenzoate (PCMB), respectively. When the substrate specificity was analyzed with tuftsin, Thr and Lys-Pro-Arg were released, and then Lys-Pro-Arg was split into Lys-Pro and Arg. Thereafter, slow liberation of Lys and Pro from Lys-Pro took place. The DFP-treated enzyme released only Thr from tuftsin and no hydrolysis of Lys-Pro-Arg was observed. With the enzyme treated with PCMB, tuftsin was converted into Thr and Lys-Pro-Arg, followed by the liberation of Arg, but no release of Lys and Pro was observed, contrary to the case of the untreated-enzyme. These results show that commercial aminopeptidase M contains dipeptidyl aminopeptidase IV and prolidase. Contamination by dipeptidyl aminopeptidase IV was confirmed by an immunological method.

Aminopeptidases↗
PubMed1982

[Comparison of the neuro- and immunomodulator properties of low-molecular neuropeptides].

A study was made of the effect of the low-molecular neuropeptides, leu- and met-enkephalins, thyroliberin (TRH), the C-end tripeptides, gastrin (MAF) and oxytocin (MIF) on the content of biogenic monoamines and their metabolites and on the production of humoral antibodies to sheep red blood cells. The action of the peptides enumerated was compared to that of the peptide immunostimulant, tuftsin. All the peptides (upon intraventricular administration) with the exception of tuftsin affect the content of brain biogenic monoamines or their metabolites. Moreover, upon intravenous injection the neuropeptides under study except met-enkephalin exert a modulating action on the immune response pattern and intensity Leu-enkephalin, MIF and MAF have immunostimulant activity similar to tuftsin. TRH given in high doses (100 and 150 mg/kg) provokes almost a two-fold decrease in the antibody titer. This peptide has an immunosuppressant effect when administered both intravenously and intracisternally. It is suggested that neuro- and immunomodulator effects have much in common at the level of cell receptors.

Adjuvants, Immunologic↗
PubMed1992

A cell attachment peptide from human C-reactive protein.

The serum acute phase reactant, C-reactive protein (CRP), is selectively deposited at sites of tissue damage and degraded by neutrophils into biologically active peptides. A synthetic peptide corresponding to residues 27-38 present in each of the five identical subunits of CRP mediated cell attachment activity in vitro. Although the CRP-derived peptide contains a Tuftsin (TKPR)-like sequence at its amino-terminus, the Tuftsin tetrapeptide itself, as well as several synthetic peptides of CRP, failed to inhibit the cell-attachment activity to the CRP-derived peptide. Peptides containing the sequences responsible for the cell attachment activity of the extracellular matrix proteins, fibronectin (Fn) and laminin, failed to inhibit the CRP-derived peptide cell attachment activity. However, the addition of the RGDS and RGDSPASSLP cell-binding peptides of Fn to cells enhanced attachment to the active peptide from CRP. In the converse experiment, the cell-binding peptide of CRP did not influence cell attachment to Fn or laminin. A peptide corresponding to the same stretch of amino acid residues within the homologous Pentraxin, serum amyloid P-component (SAP), displayed nearly identical cell-attachment activity. Several monoclonal antibodies (mAb) specific for the CRP-derived cell-binding peptide neutralized its cell-attachment activity. These mAbs reacted with intact CRP and neutralized the cell-binding activity of CRP itself. The findings suggest that a peptide with cell-binding activity could be generated from the breakdown of CRP and then contribute directly to cellular events leading to tissue repair.

Amino Acid Sequence↗
PubMed1992

Phagocytosis and microbicidal capacity of human monocytes in the course of HIV infection.

Phagocytosis and bactericidal activity of human monocytes were studied in asymptomatic HIV carriers and in patients with clinically apparent HIV infection, diagnosed as persistent generalised lymphadenopathy (PGL) or AIDS-related complex (ARC). Monocytes of asymptomatic HIV carriers manifested no significant changes while a decreased phagocytosis was shown by monocytes in the majority of patients with PGL or ARC. The latter patients also exhibited a decreased bactericidal activity of the cells. Tuftsin and even serum from healthy donors were found to normalise the disturbed monocyte function, the effect of tuftsin being more pronounced. Nevertheless, the examined sera contained neither factors which could stimulate nor factors which could inhibit phagocytosis. The obtained results indicated that the productive phase of HIV infection is associated with disturbed phagocytosis and disturbed microbicidal activity of monocytes, reflecting deficiency of serum factor(s) needed for the normal function of the cells.

AIDS-Related Complex↗
PubMed1994

Construction of a synthetic immunogen: use of the natural immunomodulator polytuftsin in malaria vaccines against RESA antigen of Plasmodium falciparum.

Polytuftsin, a 35-40-unit repeat of the naturally occurring tetrapeptide tuftsin (TKPR), was chemically linked to EENVEHDA and DDEHVEEPTVA repeat sequences of ring-infected erythrocyte surface antigen protein (an asexual blood-stage antigen) of Plasmodium falciparum. These synthetic constructs were tested for their humoral and cellular immune responses in five inbred strains of mice with different genetic backgrounds (H-2a, H-2b, H-2d, H-2k and H-2i). Mice immunized with these constructs showed higher antibody titres, secondary immune responses and antigen-induced T-cell proliferation compared with the peptide dimers alone. Sera from mice immunized with both the constructs inhibited merozoite invasion of erythrocytes in vitro by 60-80% at 1:10 antisera dilution. Polytuftsin alone proved to be a very poor immunogen in our studies, since no anti-tuftsin antibodies could be detected in the sera. Therefore, we conclude that the synthetic constructs described here could be useful for the development of subunit malaria vaccines.

Amino Acid Sequence↗
PubMed1983

Synthesis of an IgG fragment decapeptide exhibiting phagocytosis stimulating activity of polymorphonuclear leucocytes.

Fragment 335-344 of human IgG was synthesized stepwise, using active esters of N-protected amino acids and benzotriazolyloxytris (dimethylamino)phosphonium hexafluorophosphate for coupling. This fragment could be liberated from the carrier molecule by the two specific enzymes responsible for the release of tuftsin from the same carrier molecule: tuftsin endocarboxy-peptidase cleaves at the Arg-Glu bond and leukokininase at the Lys-Thr bond. This decapeptide fragment, Thr-Ile-Ser-Lys-Ala-Lys-Gly-Gln-Pro-Arg showed significant activity in stimulating phagocytosis of human polymorphonuclear leucocytes.

Immunoglobulin G↗
PubMed1988

[Comparative analysis of the morphochemical changes in the visual and sensorimotor cortical neurons of rats exposed to taftsin].

White rats were treated with a single administration of immunostimulator tuftsin (Thr-Lys-Pro-Arg, in the dose 300 mcg/kg b. w.). By interferometry protein content and concentration and the area of neuron cytoplasm and nucleus were assessed 15 minutes after injection, significant alterations in protein content and cellular area were detected in one type neurons of visual and sensomotor cortex. A possible interrelation is discussed between tuftsin action and the functional activity of neurons, and between the level of their protein metabolism and establishment of emotional and motor response.

Animals↗