Successful Therapy of Lethal Murine Visceral Leishmaniasis with Cystatin Involves Up-Regulation of Nitric Oxide and a Favorable T Cell Response

Das, Lopamudra; Datta, Neeta; Bandyopadhyay, Santu; Das, Pritha

doi:10.4049/jimmunol.166.6.4020

Cited by 109 publications

(103 citation statements)

References 40 publications

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“…Studies of null mutants have documented a role for each cathepsin in L. mexicana virulence (53,(55)(56)(57)(58). Treatment of infected mice with specific inhibitors suggests that cathepsin B of the parasite (or host) promotes disease progression (23,27,59). The mechanism through which the cathepsins promote parasite virulence was previously unknown.…”

Section: Discussionmentioning

confidence: 99%

Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages

Gantt¹,

Schultz‐Cherry

Rodríguez

et al. 2003

The Journal of Immunology

159

104

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TGF-β is a potent regulatory cytokine that suppresses expression of inducible NO synthase and IFN-γ, and suppresses Th1 and Th2 cell development. We examined whether functionally active TGF-β is present in the local environment surrounding the invading protozoan Leishmania chagasi. Our prior data showed that TGF-β levels are significantly increased in L. chagasi-infected mice. In the current study, we found TGF-β was also abundant in bone marrows of humans with acute visceral leishmaniasis but not in those of uninfected controls. Furthermore, L. chagasi infection caused an increase in biologically active TGF-β in human macrophage cultures without changing the total TGF-β. Therefore, we investigated the means through which leishmania could augment activated but not total TGF-β. Incubation of latent TGF-β with Leishmania sp. promastigotes caused active TGF-β to be released from the latent complex. In contrast, the nonpathogenic protozoan Crithidia fasciculata could not activate TGF-β. TGF-β activation by leishmania was prevented by inhibitors of cysteine proteases and by the specific cathepsin B inhibitor CA074. Physiologic concentrations of TGF-β inhibited killing of intracellular L. chagasi in macrophages, although the phagocytosis-induced respiratory burst remained intact. In contrast, supraphysiologic concentrations of TGF-β had no effect on parasite survival. We hypothesize that the combined effect of abundant TGF-β stores at extracellular sites during infection, and the ability of the parasite to activate TGF-β in its local environment, leads to high levels of active TGF-β in the vicinity of the infected macrophage. Locally activated TGF-β could, in turn, enhance parasite survival through its effects on innate and adaptive immune responses.

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Section: Discussionmentioning

confidence: 99%

Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages

Gantt¹,

Schultz‐Cherry

Rodríguez

et al. 2003

The Journal of Immunology

159

104

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“…For in vitro killing assays, adherent macrophages on glass coverslips (18 mm 2 ; 5 ϫ 10 5 macrophages/ coverslip) in 0.5 ml of RPMI 1640/10% FCS were infected with promastigotes at a ratio of 10 parasites/macrophage. Infection was allowed to proceed for 4 h, and the cells were washed to remove excess parasites, as previously described (26). Cells were then resuspended in medium with GRA for various time periods at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Adherent peritoneal macrophages (BALB/c) or the murine macrophage cell line RAW 264.7 were cultured at 37°C with 5% CO 2 in RPMI 1640 (Invitrogen Life Technologies) supplemented with 10% FCS, penicillin (100 U/ml), and streptomycin (100 g/ml). Nitrite production was determined in macrophage culture medium by the Griess reaction, as previously described (26). Cell viability was assessed using an MTT-based colorimetric assay kit (Roche) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were cultured in 96-well tissue culture plates at 4 ϫ 10 6 cells/ml and stimulated with 20 g/ml soluble leishmanial Ag (SLA) for 48 h. SLA was prepared as previously described (26). Supernatants were assayed directly using an ELISA kit (BD Pharmingen) for IL-12, IFN-␥, TNF-␣, IL-10, and IL-4, as recommended by the manufacturer.…”

Section: Analysis Of Cytokinesmentioning

confidence: 99%

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18β-Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF-κB

Ukil

Biswas

Das

et al. 2005

The Journal of Immunology

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The efficacy of 18β-glycyrrhetinic acid (GRA), a pentacyclic triterpene belonging to the β-amyrin series of plant origin, was evaluated in experimental visceral leishmaniasis. GRA is reported to have antitumor and immunoregulatory activities, which may be attributable in part to the induction of NO. Indeed, an 11-fold increase in NO production was observed with 20 μM GRA in mouse peritoneal macrophages infected with Leishmania donovani promastigotes. In addition to having appreciable inhibitory effects on amastigote multiplication within macrophages (IC50, 4.6 μg/ml), complete elimination of liver and spleen parasite burden was achieved by GRA at a dose of 50 mg/kg/day, given three times, 5 days apart, in a 45-day mouse model of visceral leishmaniasis. GRA treatment resulted in reduced levels of IL-10 and IL-4, but increased levels of IL-12, IFN-γ, TNF-α, and inducible NO synthase, reflecting a switch of CD4+ differentiation from Th2 to Th1. This treatment is likely to activate immunity, thereby imparting resistance to reinfection. GRA induced NF-κB migration into the nucleus of parasite-infected cells and caused a diminishing presence of IκB in the cytoplasm. The lower level of cytoplasmic IκBα in GRA-treated cells resulted from increased phosphorylation of IκBα and higher activity of IκB kinase (IKK). Additional experiments demonstrated that GRA does not directly affect IKK activity. These results suggest that GRA exerts its effects at some level upstream of IKK in the signaling pathway and induces the production of proinflammatory mediators through a mechanism that, at least in part, involves induction of NF-κB activation.

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“…The cells (5 Â 10 6 / mL) were stimulated with 20 mg/mL soluble leishmanial antigen (SLA) for 48 h. Splenocyte supernatant were obtained by centrifuging the culture plates and kept at À201C until further use. SLA was prepared as previously described [38]. …”

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confidence: 99%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBPbdependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4Ra) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBPb-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-Ra expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.Keywords: Arginase 1 . IL-4 . IL-10 . IL-4 receptor a . Visceral leishmaniasis IntroductionArginase is classically considered as a rate-limiting enzyme of the urea cycle in liver, but has been found to be present in a number of organs and tissues where the urea cycle is not operative. To date, two distinct isoforms of arginase have been identified in mammals. They are encoded by different genes differing in their cellular localization as well as their mode of regulation: type 1 arginase, a cytosolic enzyme expressed at high levels in liver, and type 2 arginase, a mitochondrial enzyme found in several tissues in addition to liver [1]. A growing body of evidence suggests that arginase induction is correlated with parasite-specific immunosuppression of host, thereby facilitating pathogen survival and growth inside the hostile environment of phagocytic cells. Macrophages were found to upregulate arginase 1 expression upon activation by Th2 cytokines and shown to have a detrimental role in parasite infection by limiting the Th1-dependent parasite clearance [2]. Interestingly, cAMP and TGFb are known to induce arginase 1 induction in macrophages [3]. In Chagas disease, induction of the arginase pathway could be used by Trypanosoma cruzi to spread inside host [4]. Arginase activity was triggered in macrophages from mice infected with the helminth Schistosoma mansoni and was associated with an increase in concentration of circulating L-ornithine-derived polyamines [5]. Intracellular pathogens like Salmonella enterica and Mycobacterium tuberculosis also utilize host arginase for their own 992survival within the macrophages [6,7]. Moreover, in bacteria like Helicobacter pyroli, arginase plays a major role in its surv...

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Successful Therapy of Lethal Murine Visceral Leishmaniasis with Cystatin Involves Up-Regulation of Nitric Oxide and a Favorable T Cell Response

Cited by 109 publications

References 40 publications

Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages

Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages

18β-Glycyrrhetinic Acid Triggers Curative Th1 Response and Nitric Oxide Up-Regulation in Experimental Visceral Leishmaniasis Associated with the Activation of NF-κB

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

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