Phagocytosis of Leishmania mexicana amastigotes by macrophages leads to a sustained suppression of IL-12 production

Weinheber, Nora; Wolfram, Markus; Harbecke, Dorothee; Aebischer, Toni

doi:10.1002/(sici)1521-4141(199808)28:08<2467::aid-immu2467>3.3.co;2-t

Cited by 37 publications

(53 citation statements)

References 21 publications

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“…The fact that we observed that IL-10 is upregulated in MP following Leshmania spp. infection makes it particularly appealing to implicate IL-10 as the mechanism for downregulating IL-12 expression; however, it previously has been demonstrated that inhibition still occurs in the absence of IL-10 (Carrera et al, 1996;Weinheber et al, 1998). Using a transwell system, we show here that no autocrine-or paracrine-acting MP factors are involved in suppression of IL-12 by Leishmania spp.…”

Section: Discussionmentioning

confidence: 42%

“…Reiner et al (1994) were the first to report that Leishmania major amastigotes stimulate, rather than inhibit, IL-12 production in murine bone marrow-derived MP (BMDM), an observation that was confirmed in the murine MP cell line J774 (Piedrafita et al, 1999). Conversely, Leishmania mexicana amastigotes inhibit IL-12 secretion in murine BMDM (Weinheber et al, 1998). Although L. major and Leishmania panamensis stationary-phase promastigotes induce small amounts of IL-12 secretion in human peripheral blood mononuclear cells (PBMC), these parasites, as well as Leishmania braziliensis, L. mexicana, and Leishmania guyanensis promastigotes, inhibit IL-12 release in response to SAC (Sartori et al, 1997).…”

mentioning

confidence: 98%

“…For most Leishmania species, the mechanism of IL-12 inhibition is mediated at the level of IL-12p40 mRNA accumulation (Carrera et al, 1996;Sartori et al, 1996Sartori et al, , 1997Piedrafita et al, 1999). However, steady-state IL-12p40 mRNA levels are not affected by L. mexicana infection (Weinheber et al, 1998), indicating that a posttranscriptional regulation mechanism may be occurring.Although many studies indicate that Leishmania spp. infection inhibits MP production of IL-12, several discrepancies have been reported.…”

mentioning

confidence: 99%

“…Leishmania spp.-infected MP are unable to produce IL-12 even in response to strong inflammatory stimuli, including microbial stimuli, e.g., lipopolysaccharide (LPS), Staphylococcus aureus (SAC), Toxoplasma gondii antigen, and mycobacteria (Carrera et al, 1996;Sartori et al, 1997;Belkaid et al, 1998;Weinheber et al, 1998;Piedrafita et al, 1999), and T-cell-dependent agonists, e.g., IFN-γ and CD40L (Carrera et al, 1996;Belkaid et al, 1998;Weinheber et al, 1998;Piedrafita et al, 1999). Furthermore, the inhibition observed in Leishmania spp.-infected MP is selective, that is, other proinflammatory cytokines and chemokines are not affected (Carrera et al, 1996).…”

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confidence: 99%

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Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

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To establish and persist within a host, Leishmania spp. parasites delay the onset of cell-mediated immunity by suppressing interleukin-12 (IL-12) production from host macrophages. Although it is established that Leishmania spp.-infected macrophages have impaired IL-12 production, the mechanisms that account for this suppression remain to be completely elucidated. Using a luciferase reporter assay assessing IL-12 transcription, we report here that Leishmania major, Leishmania donovani, and Leishmania chagasi inhibit IL-12 transcription in response to interferon-gamma, lipopolysaccharide, and CD40 ligand and that Leishmania spp. lipophosphoglycan, phosphoglycans, and major surface protein are not necessary for inhibition. In addition, all the Leishmania spp. strains and life-cycle stages tested inhibited IL-12 promoter activity. Our data further reveal that autocrineacting host factors play no role in the inhibitory response and that phagocytosis signaling is necessary for inhibition of IL-12.The hallmark of an intracellular pathogen is its ability to survive within the intracellular niche. These organisms must be resistant to, or able to evade, the host cell's microbiocidal mechanisms. This dilemma is particularly relevant to Leishmania spp. because these organisms primarily reside within vertebrate macrophages (MP). These host cells become activated for microbial destruction and cytokine secretion by exposure to immune modulators, such as interferon-gamma (IFN-γ) and CD40 ligand (CD40L) found on activated T-cells. One strategy Leishmania spp. parasites use to avoid host cell activation is to interfere with the signaling pathways that induce MP to become microbicidal (Gregory and Olivier, 2005); another is inhibiting or delaying the production of activating cytokines (Belkaid et al., 2000).The most consistent dysfunction reported from Leishmania spp.-infected MP is the aberrant production of inflammatory cytokines, specifically an inhibition of interleukin-12 (IL-12) production (McDowell and Sacks, 1999). Being essential for T-helper 1 (Th1) cell differentiation, the inability of Leishmania spp.-infected MP to produce IL-12 allows Leishmania spp. to evade acquired resistance by postponing IL-12 production and the induction of IFN-γ, thereby allowing the establishment of the infection; both clinical and experimental studies indicate that the onset of Th1-mediated immunity and Leishmania spp. killing is indeed delayed (Melby, 1991). Inhibition of MP IL-12 production and resulting Th1 responses is not unique to Leishmania; viruses (Chehimi et al., 1994;Chougnet et al., 1996;Karp et 1996) and bacteria (Marth and Kelsall, 1997;Sutterwala et al., 1997;Matsunaga et al., 2003) also exploit this mechanism to avoid clearance.The general nature of impaired IL-12 production in Leishmania spp.-infected MP has extended to every IL-12 agonist that has been tested. Leishmania spp.-infected MP are unable to produce IL-12 even in response to strong inflammatory stimuli, including microbial stimuli, e.g., lipopolysacchar...

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Section: Discussionmentioning

confidence: 42%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

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“…Pro-inflammatory cytokines (such as IL-12), which are essential for the generation of a successful immune response against Leishmania , are generally suppressed, facilitating a ‘silent entry’ of the parasite into host macrophages (Belkaid et al, 2000; McDowell & Sacks, 1999; Reiner, Zheng, Wang, Stowring, & Locksley, 1994; Weinheber, Wolfram, Harbecke, & Aebischer, 1998). Conversely, IL-10 which is essential for parasite survival and disease progression is induced by Leishmania in infected monocytes and macrophages (Chandra & Naik, 2008; Meddeb-Garnaoui, Zrelli, & Dellagi, 2009).…”

Section: Mechanisms Of Immune Evasionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Leishmaniasis

Gupta

Oghumu

Satoskar

2013

Advances in Applied Microbiology

214

156

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Diseases caused by Leishmania present a worldwide problem, and current therapeutic approaches are unable to achieve a sterile cure. Leishmania is able to persist in host cells by evading or exploiting host immune mechanisms. A thorough understanding of these mechanisms could lead to better strategies for effective management of Leishmania infections. Current research has focused on parasite modification of host cell signaling pathways, entry into phagocytic cells, and modulation of cytokine and chemokine profiles that alter immune cell activation and trafficking to sites of infection. Immuno-therapeutic approaches that target these mechanisms of immune evasion by Leishmania offer promising areas for preclinical and clinical research.

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Silent infection of bone marrow-derived dendritic cells byLeishmania mexicana amastigotes

et al. 2001

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Resolution of infection by Leishmania sp. is critically dependent on activation of CD4+ T helper cells. Naive CD4+ T helper cells are primed by dendritic cells which have responded to an activation signal in the periphery. However, the role of Leishmania‐infected dendritic cells in the activation of an anti‐Leishmania immune response has not been comprehensively addressed. Using the highly controlled model system of bone marrow‐derived dendritic cell infection by Leishmania mexicana cultured in vitro, we show that uptake of L. mexicana parasites does not result in activation of immature dendritic cells or secretion of IL‐12. Incubation with L. mexicana promastigotes results in the activation of a small percentage of dendritic cells which do not appear to contain whole parasites. Activation of dendritic cells is not suppressed by infection, since infected cells can be fully activated on addition of activating stimuli. Therefore, uptake of intact Leishmania mexicana parasites is not sufficient to activate dendritic cells in vitro. We propose that these data provide a basis for interpreting the interactions between dendritic cells and all Leishmania sp.

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Phagocytosis of Leishmania mexicana amastigotes by macrophages leads to a sustained suppression of IL-12 production

Cited by 37 publications

References 21 publications

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

Mechanisms of Immune Evasion in Leishmaniasis

Silent infection of bone marrow-derived dendritic cells byLeishmania mexicana amastigotes

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