Impaired Expression of Inflammatory Cytokines and Chemokines at Early Stages of Infection with<i>Leishmania amazonensis</i>

Ji, Jiaxiang; Sun, Jiaren; Soong, Lynn

doi:10.1128/iai.71.8.4278-4288.2003

Cited by 153 publications

(209 citation statements)

References 56 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…Although IL-10-deficient mice were more resistant to L. major (Brooks et al, 2006;Kane and Mosser, 2001), deletion of the IL-10 gene did not change the susceptibility of mice to La parasites (Jones et al, 2002), suggesting to us that an IL-10-independent mechanism in persistent infection is caused by La infection. Accordingly, this study supports the view that amastigotes in the L. mexicana complex (La, L. mexicana, and L. pifanoi) can directly suppress the activation and/or accelerate the degradation of signaling pathways via their peptidases/ proteinases (Cameron et al, 2004), and that this delayed and suppressed DC activation is responsible for impaired innate and acquired immunity to parasite infection (Ji et al, 2003;Xin et al, 2007).…”

Section: Discussionsupporting

confidence: 85%

“…However, we and others have found that La infection results in nonhealing disease in most inbred mouse strains due to the induction of a weak, Th1/Th2 mixed response (Ji et al, 2002;Jones et al, 2000). The deficient Th1 response seen in La-infected mice is due largely to profound, multiple impairments in numerous cytokines, chemokines, and their corresponding receptors at an early stage of the infection (Ji et al, 2003). Our recent evidence of intrinsic defects in La-infected DCs support the concept that Leishmania parasites can manipulate the immune response at the APC level (Xin et al, 2007).…”

Section: Introductionmentioning

confidence: 73%

“…In contrast to induction of DC activation and upregulation of IL-12 production by L. major, non-healing La infection induced impaired DC maturation/activation and cytokine production, which correlated with profoundly impaired, multiple immune responses at an early stage of the infection (Favali et al, 2007;Ji et al, 2003;Xin et al, 2007). However, the precise molecular mechanism(s) by which La modulates DC function remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…1A). Since the JAK/STAT signaling pathway is important for DC differentiation/maturation and innate immunity (Shuai and Liu, 2003), we speculated that weak activation and dysregulation of this pathway may account for insufficient DC activation and T cell priming during La infection (Ji et al, 2003;Xin et al, 2007). Analyses of the expression of genes in the JAK/STAT signaling pathway using Oligo GEArray revealed that nearly 55 out of 120 tested genes were induced in both groups of infected DCs in comparison to control (data not shown).…”

Section: Amazonensis Infection Modulates DC Function and Cytokine mentioning

confidence: 99%

“…We have previously shown that profound impairment in cytokine/chemokine expression during La infection (Ji et al, 2003) was mostly due to intrinsic defects in DC activation (Xin et al, 2007), and, thus, we sought to explore the underlying mechanisms in the present study. First, we confirmed that DCs infected with La promastigotes (Pm) produced significantly lower levels of IL-12p40 and IL-10 than did control cells infected with L. major (Spl.…”

Section: Amazonensis Infection Modulates DC Function and Cytokine mentioning

confidence: 99%

See 4 more Smart Citations

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Luo

Soong

2008

Molecular Immunology

Self Cite

View full text Add to dashboard Cite

We have previously reported a link between a deficient Th1 response to Leishmania amazonensis (La) parasites and profound impairments in the cytokine/chemokine network at early stages of the infection. To define the molecular basis of these deficiencies, we focused on early and intracellular events in La-infected dendritic cells (DCs) in this study. Compared with La promastigote-infected counterparts, amastigote-infected DCs were less mature and less potent as antigen-presenting cells (APC) as evidenced by the lower expression of CD40 and CD83, suppressed cytokine expression (IL-12p40 and IL-10), reduced effectiveness for priming CD4 + T cells from naïve or infected mice. Infection with La promastigotes, but not amastigotes, triggered transient expression of IL-12p40 by DC. Both forms of parasites markedly suppressed IL-12p40, IL-12p70, and IL-6 production and increased IL-10 production when DCs were treated with LPS, IFN-γ/LPS or IFN-α/LPS as positive stimuli. Of note, pre-infection of DCs with live amastigotes resulted in multiple alterations in innate signaling pathways, including degradation of STAT2, decreased phosphorylation of STAT1, 2, 3 and ERK1/2, and markedly reduced expression of interferon regulatory factor-1 (IRF-1) and IRF-8, some of which were partially reversed by pretreatment of parasites with proteasome or protease inhibitors. The impaired IL-12 production in infected DCs was not attributed to increased IL-10 production. Together, our data suggest that La parasites, especially in their intracellular forms, have evolved unique strategies to actively downregulate early innate signaling events, resulting in impaired DC function and Th1 activation.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Amazonensis Infection Modulates DC Function and Cytokine mentioning

confidence: 99%

Section: Amazonensis Infection Modulates DC Function and Cytokine mentioning

confidence: 99%

See 3 more Smart Citations

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Luo

Soong

2008

Molecular Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

NTPDase activities: possible roles on Leishmania spp infectivity and virulence

Paes-Vieira

Gomes-Vieira

Meyer‐Fernandes

2018

Cell Biology International

View full text Add to dashboard Cite

Nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes that belong to the GDA1/CD39 protein superfamily. These enzymes catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP). Biochemical characterization of the nucleotidases/NTPDases from various types of cells, including those from plants, animals, and pathogenic organisms, has revealed the existence of several isoforms with different specificities with respect to divalent cations (magnesium, calcium, manganese, and zinc) and substrates. In mammals, the NTPDases play important roles in the regulation of thrombosis and inflammation. In parasites of the genus Leishmania, the causative agents of leishmaniasis, two NTPDase isoforms, termed NTPDase-1 and NTPDase-2 have been described. Independently of their cellular localization, whether cell-surface localized, secreted or targeted to other organelles, in some Leishmania species these NTPDases could be involved in parasite growth, infectivity, and virulence. Experimental evidence has suggested that the hydrolysis of ATP and ADP by parasite ecto-nucleotidases can down-modulate the host immune response. In this context, the present work provides an overview of recent works that show strong evidence not only of the involvement of the nucleotidases/NTPDases in Leishmania spp infectivity and virulence but also of the molecular mechanisms that lead to the success of the parasitic infection.

show abstract

Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism

et al. 2018

View full text Add to dashboard Cite

The induced expression of nitric oxide synthase (iNOS) controls the intracellular growth of Leishmania in infected macrophages. Histones deacetylases (HDACs) negatively regulate gene expression through the formation of complexes containing transcription factors such as NF-κB p50/50. Herein, we demonstrated the occupancy of p50/p50_HDAC1 to iNOS promoter associated with reduced levels of H3K9Ac. Remarkably, we found increased levels of HDAC1 in L. amazonensis-infected macrophages. HDAC1 upregulation was not found in L. major-infected macrophages. The parasite intracellular load was reduced in HDAC1 knocked-down macrophages, which presented increased nitric oxide levels. HDAC1 silencing led to the occupancy of CBP/p300 to iNOS promoter and the rise of H3K9Ac modification. Importantly, the immunostaining of skin samples from hiporeactive cutaneous leishmaniasis patients infected with L. amazonensis, revealed high levels of HDAC1. In brief, L. amazonensis induces HDAC1 in infected macrophages, which contribute to parasite survival and is associated to hiporeactive stage found in L. amazonensis infected patients.

show abstract

Impaired Expression of Inflammatory Cytokines and Chemokines at Early Stages of Infection withLeishmania amazonensis

Abstract: Infection of mice with

Cited by 153 publications

References 56 publications

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

NTPDase activities: possible roles on Leishmania spp infectivity and virulence

Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism

Contact Info

Product

Resources

About