The macrophage-activating tetrapeptide tuftsin induces nitric oxide synthesis and stimulates murine macrophages to kill Leishmania parasites in vitro

Cillari, Enrìco; Arcoleo, Francesco; Dieli, Maria; D'Agostino, Rita; Gromo, Gianni; Leoni, Flavio; Milano, Salvatore

doi:10.1128/iai.62.6.2649-2652.1994

Cited by 29 publications

(11 citation statements)

References 25 publications

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“…Furthermore, these retro-inverso CRP-related analogues display potent immunostimulating activities. In particular, retro-inverso CRP analogues enhanced NO production induced by suboptimal amounts of LPS (1 mg ml 71 ) and increased iNOS activity in peritoneal macrophages as observed for tuftsin (Cillari et al, 1994). The enhanced eect of retroinverso CRP-related analogues on the expression of iNOS is highlighted both by higher levels of iNOS activity and by the increase of protein mass for iNOS, evaluated by Western blot analysis in stimulated macrophages.…”

Section: Discussionmentioning

confidence: 75%

Effect of partially modified retro‐inverso analogues derived from C‐reactive protein on the induction of nitric oxide synthesis in peritoneal macrophages

Arcoleo¹,

Milano²,

D’Agostino³

et al. 1997

British J Pharmacology

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1 The ability of three modi®ed tetrapeptides, representing fragments of the C-reactive protein (CRP) sequence and stabilized in the ®rst peptide bond by retro-inverso modi®cation, to a ect the secretion of nitric oxide (NO) was studied in macrophages of BALB/c mice. 2 These tetrapeptides, resembling the aminoacid sequence of tuftsin (CRP I, H-gThr-(R,S)mLys-ProLeu-OH, ITF 1192; CRP II, H-gGly-(R, S)mLys-Pro-Arg-OH, ITF 1127; CRP III, H-gThr-(R,S)mLysPro-Gln-OH, ITF 1193), were able to induce NO synthesis by peritoneal macrophages in a dosedependent manner; the most stimulating dose was 1000 ng ml 71 for CRP II and 100 ng ml 71 for CRP I and CRP III. NO synthesis was not strictly dependent on lipopolysaccharide (LPS) activation. 3 The enhanced e ect of retro-inverso CRP-related analogues on the expression of iNOS (inducible NO synthase) was con®rmed by higher levels of iNOS activity in the cytosol and by the increase in iNOS protein, as evaluated by Western blot analysis, in macrophages stimulated by CPR compared with untreated ones. 4 The production of NO by retro-inverso CRP-peptide analogues was signi®cantly inhibited by dexamethasone (20 mM), N G -monomethyl-L-arginine (L-NMMA) (500 mM) and pyrrolidine dithiocarbamate (PDTC) (100 mM). 5 Retro-inverso CRP-peptide analogues stimulated macrophages to produce high levels of interleukin-1 (IL-1) and tumour necrosis factor-a (TNF-a) in the presence of LPS. 6 Retro-inverso CRP-peptide analogues stimulated NO synthesis by the enhancement of endogenously produced IL-1 and TNF-a, as the treatment of peritoneal macrophages with LPS in the presence of neutralizing anti-IL-1 and anti-TNF monoclonal antibodies (mAbs) reduced retro-inverso analogueinduced NO secretion. Data indicate a predominant role for IL-1a in the induction of NO secretion by retro-inverso analogues. 7 These results suggest that retro-inverso CRP derived analogues act as costimulators of NO and cytokine synthesis in macrophages. The mechanisms by which they cause iNOS induction appear to be strongly dependent on the activation of nuclear factor-kB (NF-kB).

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Section: Discussionmentioning

confidence: 75%

Effect of partially modified retro‐inverso analogues derived from C‐reactive protein on the induction of nitric oxide synthesis in peritoneal macrophages

Arcoleo¹,

Milano²,

D’Agostino³

et al. 1997

British J Pharmacology

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“…Three isoforms of NOS have been cloned (18,36). The Ca 2ϩ -independent isoform (iNOS), which is generated by the exposition of cells to immune or inflammatory stimuli, is expressed in the widest variety of cells (7,24,40). The iNOS isoform is associated with tissue damage in septic shock (28), and it has been demonstrated that the in vivo administration of LPS to mice results in the production of TNF-␣ and IL-1, which could induce the differential expression of iNOS in the lung, heart, and spleen (8).…”

mentioning

confidence: 99%

Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood

Milano

Arcoleo

D’Agostino

et al. 1997

Antimicrob Agents Chemother

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We have tested whether tetracyclines (TETs) are able to protect mice from lipopolysaccharide (LPS)-induced shock, a cytokine-mediated inflammatory reaction. Mice, injected with a single dose of tetracycline base (TETb; 1.5, 10 and 20 mg/kg of body weight) or doxycycline (DOXY; 1.5 mg/kg), were significantly protected from a lethal intraperitoneal injection of LPS (500 micrograms per mouse). TETs acted in early events triggered in response to LSP; in fact, they were no longer significantly protective if injected more than 1 h after the injection of endotoxin. LPS-treated mice protected by TETs showed a significant inhibition of tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and nitrate secretion in the blood, events that were directly related with the survival. In mice treated with TETs a significant decrease of inducible nitric oxide synthase (iNOS) activity was observed in spleen and peritoneal cells compared with that detected in mice treated with LPS alone. Furthermore, TETs were found to inhibit NO synthesis by peritoneal macrophages stimulated in vitro with LPS. On the contrary, TETs were unable to decrease the ability of the macrophages to synthesize IL-1 alpha and TNF-alpha in vitro. These results indicate that TETs are not able to act directly on the synthesis of these cytokines, but they may modulate other pathways that could in turn be responsible for the inhibition of IL-1 alpha and TNF-alpha synthesis. Altogether, these results indicate that TETs are advantageous candidates for the prophylaxis and treatment of septic shock in mice, having both antimicrobial activity and the ability to inhibit endogenous TNF-alpha, IL-1 alpha, and iNOS, hence, exerting, potent anti-inflammatory effects.

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“…The immunomodulator tuftsin induces respiratory burst phenomenon in macrophages, and activated macrophages exhibited enhanced levels of NADPH oxidase, O 2 , H 2 O 2 and myeloperoxidase (Cillari et al, 1994). Both O 2 and H 2 O 2 damage proteins, nucleic acids and membranes sufficiently to kill the pathogens.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic use of liposomized tuftsin enhances the susceptibility ofCandida albicansto fluconazole in leukopenic mice

Khan

Owais

2006

FEMS Immunology &Amp; Medical Microbiology

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In the present study, we investigated the immunopotentiating activity of the immunomodulator tuftsin for the treatment of dose-dependent susceptible Candida albicans infection in a murine model. Our results demonstrated that tuftsin increases the susceptibility of C. albicans to phagocytosis by activating murine macrophages. Fluconazole used for the treatment of mice infected with C. albicans showed less in vivo efficacy and proved to be ineffective in the elimination of the infection from leukopenic mice even at higher doses. However, the antifungal activity of fluconazole against the same isolate of C. albicans significantly increased in tuftsin-pretreated mice and resulted in an improved survival rate in mice. The treated mice also showed less severity of infection as supported by a reduced fungal burden in their kidneys. This study indicates that the use of immunopotentiating substances can enhance the therapeutic efficacy of azole antifungal agents and thus can effectively combat azole-resistant fungal pathogens under conditions of immunosuppression.

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The macrophage-activating tetrapeptide tuftsin induces nitric oxide synthesis and stimulates murine macrophages to kill Leishmania parasites in vitro

Cited by 29 publications

References 25 publications

Effect of partially modified retro‐inverso analogues derived from C‐reactive protein on the induction of nitric oxide synthesis in peritoneal macrophages

Effect of partially modified retro‐inverso analogues derived from C‐reactive protein on the induction of nitric oxide synthesis in peritoneal macrophages

Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood

Prophylactic use of liposomized tuftsin enhances the susceptibility ofCandida albicansto fluconazole in leukopenic mice

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