In Vivo Activation of Macrophages but not Natural Killer Cells by Picolinic Acid (Pla)

Ruffmann, R; Welker, Roy D.; Saito, Tohru; Chirigos, Michael A.; Varesio, Luigi

doi:10.3109/08923978409028605

Cited by 21 publications

(19 citation statements)

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“…In particular, the macrophage compartment promptly responds to PLA as shown by in vitro and in vivo experimental models (27,29 Moreover, PLA administration is associated with a local response in terms of enhanced levels of mRNA specific for IL-1 and TNF in brain tissues.…”

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“…administration of exogenous IL-1 produces a significant enhancement of local anti-Candida resistance, in terms of both increased survival to the lethal challenge and reduced CFU recovery from the brain. Overall, these findings imply that macrophage-mediated effector as well as secretory functions are precious innate mechanisms involved in local antimicrobial defense(s) in the brain compartment.Picolinic acid (PLA), a naturally occurring product of tryptophan catabolism, is endowed with a variety of effects on ion traffic (8, 9), cell cycle (10, 15), bacterial growth (7,11), and host immune responses (27,29). In particular, the macrophage compartment promptly responds to PLA as shown by in vitro and in vivo experimental models (27,29 Moreover, PLA administration is associated with a local response in terms of enhanced levels of mRNA specific for IL-1 and TNF in brain tissues.…”

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confidence: 99%

“…Picolinic acid (PLA), a naturally occurring product of tryptophan catabolism, is endowed with a variety of effects on ion traffic (8, 9), cell cycle (10, 15), bacterial growth (7,11), and host immune responses (27,29). In particular, the macrophage compartment promptly responds to PLA as shown by in vitro and in vivo experimental models (27,29 Moreover, PLA administration is associated with a local response in terms of enhanced levels of mRNA specific for IL-1 and TNF in brain tissues.…”

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Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans

Blasi

Mazzolla

Pitzurra

et al. 1993

Antimicrob Agents Chemother

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We have studied the effects of picolinic acid (PIA), a product of tryptophan degradation, on mouse susceptibility to intracerebral infection with Candida albicans. We (1,3). In particular, i.c. transfer of an in vitro-established microglial cell line into syngeneic mice confers local protection against subsequent lethal challenge with C. albicans (3). Furthermore, increasing evidence exists on the role of cytokines in the immune and inflammatory responses during brain infections or injuries (24). In particular, tumor necrosis factor (TNF), interleukin 1 (IL-1), and IL-6 are produced locally and likely have an immunomodulatory function(s) during meningococcal infections (30). Direct proof for IL-1 as an immunopotentiating cytokine at the cerebral level has been provided (19), since i.c. administration of exogenous IL-1 produces a significant enhancement of local anti-Candida resistance, in terms of both increased survival to the lethal challenge and reduced CFU recovery from the brain. Overall, these findings imply that macrophage-mediated effector as well as secretory functions are precious innate mechanisms involved in local antimicrobial defense(s) in the brain compartment.Picolinic acid (PLA), a naturally occurring product of tryptophan catabolism, is endowed with a variety of effects on ion traffic (8, 9), cell cycle (10, 15), bacterial growth (7,11), and host immune responses (27,29). In particular, the macrophage compartment promptly responds to PLA as shown by in vitro and in vivo experimental models (27,29 Moreover, PLA administration is associated with a local response in terms of enhanced levels of mRNA specific for IL-1 and TNF in brain tissues. MATERIALS AND METHODSMice. Female C57BL/6 (H-2") mice, 6 to 8 weeks old, were obtained from Charles River Breeding Laboratories, Calco, Milan, Italy.Drugs. Alpha-PLA (approximately 99% pure) and pyridine-4-carboxylic acid (PCA) were purchased from Sigma Chemical Co., St. Louis, Mo. Stock solutions, prepared with sterile pyrogen-free saline, were tested for endotoxin contamination by Limulus amebocyte lysate assay. Only preparations with undetectable endotoxin levels (less than 0.5 ng/ml) were stored at -80°C and used in the experiments described.C. albicans. The strain of C. albicans serotype A used throughout this study was a kind gift of D. Kerridge,

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Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans

Blasi

Mazzolla

Pitzurra

et al. 1993

Antimicrob Agents Chemother

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“…This molecule is able to form stable complexes with transition metal ions (24), and its chelating properties seem to facilitate the absorption of zinc from the intestine (25) and explain the inhibitory effect of PA in the axenic growth of Escherichia coli (26) as well as in the growth of normal kidney rat cells (27,28). PA is also tumoricidal in vivo (29), an effect that is related to the induction of macrophage-mediated cytostatic activity (30). The idea that PA plays a role in immune mechanisms is strengthened by the observation that mice treated with PA have enhanced levels of mRNA for IL-1 and TNF-␣ and higher resistance to Candida albicans (31).…”

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Macrophage Control of Mycobacterial Growth Induced by Picolinic Acid Is Dependent on Host Cell Apoptosis

Pais

Appelberg

2000

The Journal of Immunology

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The effects of picolinic acid (PA) on the intramacrophagic growth of Mycobacterium avium were studied. PA reduced M. avium growth inside mouse macrophages and led to a complete control of mycobacterial growth when added together with IFN-γ. The mechanism involved did not require TNF-α, NO, or the respiratory burst, and was not dependent on either iron or zinc withholding. The mycobacteriostatic activity of the macrophages was associated with the induction of morphological changes that culminated in apoptosis at day 4 of treatment. PA alone induced apoptosis in macrophages, and this effect was increased by IFN-γ treatment. Apoptosis at day 4 of infection was reduced by inhibiting macrophage activation with the prostaglandin 15 deoxy-prostaglandin J2 or by treating the cells with the antioxidant N-acetylcysteine. Mycobacterial growth was partially restored in macrophages treated with PA and IFN-γ when 15 deoxy-prostaglandin J2 was added, concomitant with a delay in apoptosis. N-Acetylcysteine or glutathione could also completely revert the mycobacteriostatic effects of PA or PA plus IFN-γ.

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“…The induction of anti-M. avium activity was closely associated with the induction of apoptosis which occurred over a protracted period of a few days. PA is also a co-stimulator of macrophage tumoricidal and antimicrobial activities (Blasi et al, 1993;Leuthauser et al, 1982;Ruffmann et al, 1984;Varesio et al, 1990). …”

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Induction of Mycobacterium avium growth restriction and inhibition of phagosome–endosome interactions during macrophage activation and apoptosis induction by picolinic acid plus IFNγ

Pais¹,

Appelberg²

2004

Microbiology

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Treatment of mouse macrophages with picolinic acid (PA) and c-interferon (IFNc) led to the restriction of Mycobacterium avium proliferation concomitant with the sequential acquisition of metabolic changes typical of apoptosis, mitochondrial depolarization, annexin V staining and caspase activation, over a period of up to 5 days. However, triggering of cell death by ATP, staurosporine or H 2 O 2 failed to affect mycobacterial viability. In contrast to untreated macrophages where extensive interactions between phagosomes and endosomes were observed, phagosomes from treated macrophages lost the ability to acquire endosomal dextran. N-Acetylcysteine was able to revert both the anti-mycobacterial activity of treated macrophages as well as the block in phagosome-endosome interactions. The treatment, however, induced only a minor increase in the acquisition of lysosomal markers, namely Lamp-1, and did not increase to any great extent the acidification of the phagosomes. These data thus suggest that the anti-mycobacterial activity of PA and IFNc depends on the interruption of intracellular vesicular trafficking, namely the blocking of acquisition of endosomal material by the microbe. INTRODUCTIONMycobacterium avium is an opportunistic pathogen that infects patients suffering from local or systemic deficiencies of the immune system (Falkinham, 1996). Resistance to infection is dependent on both innate mechanisms and acquired immunity through the development of antigenspecific CD4 + T cells (Appelberg, 1994;Holland, 1996). M. avium replicates inside the macrophage and is particularly resistant to the oxidative antimicrobial mechanisms of this phagocyte (Gomes & Appelberg, 2002;Gomes et al., 1999a). Like other pathogenic mycobacteria, M. avium has evolved survival strategies that interfere with the normal intracellular trafficking of vesicular compartments. After being internalized by macrophages, mycobacteria inhibit the fusion of the vacuole they inhabit with lysosomes, thus blocking maturation of the phagosomes into phagolysosomes and proliferating in vacuoles with early endosomal characteristics (Armstrong & d'Arcy-Hart, 1971;Clemens & Horwitz, 1995;Frehel et al., 1986;Russell et al., 1997). Several mechanisms associated with this inhibition have been described, such as reduced phagosomal acidification (Crowle et al., 1991;Sturgill-Koszycki et al., 1994;de Chastellier et al., 1995) due to exclusion of the vacuolar H + -ATPase , altered signalling pathways (Malik et al., 2001;Fratti et al., 2003), interference with the recycling of Rab proteins (Via et al., 1997), retention of the actin-binding coronin/TACO protein (Ferrari et al., 1999; see also Schuller et al., 2001, for a critical reappraisal of this issue), disorganization of the actin filament network (Guérin & de Chastellier, 2000) and tight apposition of the membrane vacuole to the surface of the pathogen, leading to altered exchange of fusion factors (de Chastellier & Thilo, 1997). However, mycobacterial phagosomes keep their ability to interact extensively wi...

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In Vivo Activation of Macrophages but not Natural Killer Cells by Picolinic Acid (Pla)

Cited by 21 publications

References 14 publications

Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans

Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans

Macrophage Control of Mycobacterial Growth Induced by Picolinic Acid Is Dependent on Host Cell Apoptosis

Induction of Mycobacterium avium growth restriction and inhibition of phagosome–endosome interactions during macrophage activation and apoptosis induction by picolinic acid plus IFNγ

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