Cystatin cures visceral leishmaniasis by NF‐κB‐mediated proinflammatory response through co‐ordination of TLR/MyD88 signaling with p105‐Tpl2‐ERK pathway

Kar, Susanta Kumar; Ukil, Anindita; Das, Pritha

doi:10.1002/eji.201040533

Cited by 34 publications

(21 citation statements)

References 46 publications

(84 reference statements)

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“…IKK activity was measured as described previously (25). Briefly, cells were lysed in lysis buffer (Cell Signaling Technology), and the supernatant was obtained by centrifugation at 12,000 3 g for 10 min at 4˚C.…”

Section: Ikk Assaymentioning

confidence: 99%

“…Cells were harvested using reporter lysis buffer (Promega), and NF-kB luciferase activity was assessed via luminometry as previously described (25). For small interfering RNA (siRNA) transfection, RAW 264.7 cells (2 3 10 6 ) were transfected with 1 mg A20 siRNA or control siRNA according to the manufacturer's instructions (Santa Cruz Biotechnology).…”

Section: Transient Transfection and Nf-kb Reporter Assaymentioning

confidence: 99%

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Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Srivastav

Kar

Chande

et al. 2012

The Journal of Immunology

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TLRs, which form an interface between mammalian host and microbe, play a key role in pathogen recognition and initiation of proinflammatory response thus stimulating antimicrobial activity and host survival. However, certain intracellular pathogens such as Leishmania can successfully manipulate the TLR signaling, thus hijacking the defensive strategies of the host. Despite the presence of lipophosphoglycan, a TLR2 ligand capable of eliciting host-defensive cytokine response, on the surface of Leishmania, the strategies adopted by the parasite to silence the TLR2-mediated proinflammatory response is not understood. In this study, we showed that Leishmania donovani modulates the TLR2-mediated pathway in macrophages through inhibition of the IKK–NF-κB cascade and suppression of IL-12 and TNF-α production. This may be due to impairment of the association of TRAF6 with the TAK–TAB complex, thus inhibiting the recruitment of TRAF6 in TLR2 signaling. L. donovani infection drastically reduced Lys 63-linked ubiquitination of TRAF6, and the deubiquitinating enzyme A20 was found to be significantly upregulated in infected macrophages. Small interfering RNA-mediated silencing of A20 restored the Lys 63-linked ubiquitination of TRAF6 as well as IL-12 and TNF-α levels with a concomitant decrease in IL-10 and TGF-β synthesis in infected macrophages. Knockdown of A20 led to lower parasite survival within macrophages. Moreover, in vivo silencing of A20 by short hairpin RNA in BALB/c mice led to increased NF-κB DNA binding and host-protective proinflammatory cytokine response resulting in effective parasite clearance. These results suggest that L. donovani might exploit host A20 to inhibit the TLR2-mediated proinflammatory gene expression, thus escaping the immune responses of the host.

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Section: Ikk Assaymentioning

confidence: 99%

Section: Transient Transfection and Nf-kb Reporter Assaymentioning

confidence: 99%

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Srivastav

Kar

Chande

et al. 2012

The Journal of Immunology

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“…The dosage of BAY was determined according to previous studies (14,15). BAY was dissolved in 10% dimethyl sulfoxide (DMSO)/phosphate-buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

NF-κB inhibition alleviates carbon tetrachloride-induced liver fibrosis via suppression of activated hepatic stellate cells

Wang

Liu

et al. 2014

Experimental and Therapeutic Medicine

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An effective treatment for hepatic fibrosis is not available clinically. Nuclear factor (NF)-κB plays a central role in inflammation and fibrosis. The aim of the present study was to investigate the effect of an NF-κB inhibitor, BAY-11–7082 (BAY), on mouse liver fibrosis. The effects of BAY on hepatic stellate cell (HSC) activation were measured in the lipopolysaccharide-activated rat HSC-T6 cell line. In addition, the therapeutic effect of BAY was studied in vivo using a model of hepatic fibrosis induced by carbon tetrachloride (CCl4) in mice. BAY effectively decreased the cell viability of activated HSC-T6 cells and suppressed HSC-T6 activation by downregulating the expression of collagen I and α-smooth muscle actin. BAY significantly inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) in activated HSC-T6 cells. In addition, administration of BAY attenuated mouse liver fibrosis induced by CCl4, as shown by histology and the expression of profibrogenic markers. BAY also significantly decreased the levels of serum alanine aminotransferase in this model of hepatic fibrosis. Therefore, the results of the present study demonstrate that BAY attenuates liver fibrosis by blocking PI3K and Akt phosphorylation in activated HSCs. Thus, BAY demonstrates therapeutic potential as a treatment for hepatic fibrosis.

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“…Our studies also revealed that the Mitogen-activated protein kinase kinase -extracellular signal regulated kinases(MEK-ERK ) pathway. pathway is compensated in infected cells [33]. GRA, the triterpenoid is an ideal candidate both because of its pharmacologically safe parameters and immunomodulatory properties [19].…”

Section: Mapk and Phosphatasesmentioning

confidence: 99%

Bioactive Component of Licorice as an Antileishmanial Agent

Gupta¹,

Ukil²,

Das³

2017

Biological Activities and Action Mechanisms of Licorice Ingredients

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The term leishmaniasis encompasses a spectrum of vector-borne protozoan parasitic diseases ranging from self-healing cutaneous to fatal visceral leishmaniasis. The disease affects 12 million people worldwide with 0.5 million new cases per annum. Present antileishmanial chemotherapeutic drugs project limitations because of severe toxicity, lengthy regime and occurrence of resistance, thereby making development of newer, gentler and efficacious therapeutics an urgent need for treatment of leishmaniasis. Application of medicinal plants in treatment of refractory diseases is valued for its clinical efficacy and nontoxicity. The biologically active components derived from them continue to play important roles as chemopreventive agents. Licorice has been known for its medicinal property from ancient times for treatment of various ailments. 18β-Glycyrrhetinic acid, glycyrrhizic acid and licochalcone A are the most extensively studied constituents of licorice in terms of antileishmanial agent. Overall, this chapter is dedicated to highlight the current understanding of the mechanism of these bioactive constituents of licorice, which potentiates them as antileishmanial agents. Furthermore, it also brings to light the importance of folk medicine in curing diseases and thereby gives impetus to explore ancient medicines and thier mode of actions to use them progressively to cure diseases.

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Cystatin cures visceral leishmaniasis by NF‐κB‐mediated proinflammatory response through co‐ordination of TLR/MyD88 signaling with p105‐Tpl2‐ERK pathway

Cited by 34 publications

References 46 publications

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

NF-κB inhibition alleviates carbon tetrachloride-induced liver fibrosis via suppression of activated hepatic stellate cells

Bioactive Component of Licorice as an Antileishmanial Agent

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