Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans

Piedrafita, David; Proudfoot, Lorna; Nikolaev, Andrei V.; Xu, Damo; Sands, William A.; Feng, Gui-Jie; Thomas, Elaine R.; Brewer, James M.; Ferguson, Michael A. J.; Alexander, James; Liew, Foo Y.

doi:10.1002/(sici)1521-4141(199901)29:01<235::aid-immu235>3.3.co;2-j

Cited by 38 publications

(62 citation statements)

References 31 publications

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“…The ratio of IL-4:IFN-c-producing cells was also biased toward inflammation during protection, whereas IL-4 was the dominant cytokine during parasitemia. Th1-type responses also control Leishmania major but Th2-type responses exacerbate the disease [27]. This is consistent with our observation [7] that IFN-c-producing liver CD8 T cells increase between 1 and 6 h after challenge of cspz-immune mice.…”

Section: Discussionsupporting

confidence: 91%

“…The selective down-regulation of MHC class I on and the absence of early IL-12 production by KC from naivechallenged mice suggest that spz-induced inhibition targeted predominantly MHC class I and inflammatory cytokines, as reported in other systems [27]. MHC class I and inflammatory cytokines are sine qua non for the activation of Ag-specific effector CD8 T cells, which are not detected in spz-challenged naive mice [7].…”

Section: Discussionmentioning

confidence: 69%

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The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

Steers

Schwenk

Bacon³

et al. 2005

Eur. J. Immunol.

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Multi-factorial immune mechanisms underlie protection induced with radiationattenuated Plasmodia sporozoites (c-spz). Spz pass through Kupffer cells (KC) before invading hepatocytes but the involvement of KC in protection is poorly understood. In this study we investigated whether c-spz-immune KC respond to infectious spz in a manner that is distinct from the response of naive KC to infectious spz. KC were isolated from (1) naive, (2) spz-infected, (3) c-spz-immune, and (4) c-spz-immune-challenged C57BL/6 mice and examined for the expression of MHC class I and II, CD40 and CD80/CD86, IL-10 and IL-12 responses and antigen-presenting cell (APC) function. KC from c-spz-immune-challenged mice up-regulated class I and costimulatory molecules and produced elevated IL-12p40, relative to naive KC. In contrast, KC from naive mice exposed to infectious spz down-modulated class I and IL-12p40 was undetectable. Accordingly, KC from spz-infected mice had reduced APC function, while KC from c-spz-immune-challenged mice exhibited augmented APC activity. The nearly opposite responses are consistent with the fact that spz challenge of c-spz-immune mice results in long-lasting sterile protection, while infection of naive mice always results in malaria.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 69%

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

Steers

Schwenk

Bacon³

et al. 2005

Eur. J. Immunol.

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Section: Introductionmentioning

confidence: 97%

“…Specifically, both purified and synthetic phosphoglycans (PG) have been reported to inhibit IL-12 production in murine MP (Piedrafita et al, 1999). The leishmanial surface expresses other molecules that interact with the host cell, such as lipophosphoglycan (LPG), glycosylinositol phospholipids (Orlandi and Turco, 1987;McConville et al, 1995), and a surface protease (GP63, MSP) (Guha-Niyogi et al, 2001), that may mediate IL-12 inhibition.…”

Section: Introductionmentioning

confidence: 99%

“…life-cycle stages in the inhibitory process. 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 (Carrera et al, 1996).The fact that Leishmania spp.-conditioned medium is able to inhibit SAC-induced IL-12 production in human PBMC (Sartori et al, 1997) suggests that soluble parasite components mediate IL-12 inhibition. Specifically, both purified and synthetic phosphoglycans (PG) have been reported to inhibit IL-12 production in murine MP (Piedrafita et al, 1999).…”

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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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Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages

Privé¹,

Descoteaux²

2000

Eur. J. Immunol.

138

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The protozoan parasite Leishmania fails to activate naive macrophages for proinflammatory cytokines production, and selectively impairs signal transduction pathways in infected macrophages. Because mitogen‐activated protein kinases (MAPK)‐ and NF‐κB‐dependent signaling pathways regulate proinflammatory cytokines release, we investigated their activation in mouse bone marrow‐derived macrophages (BMM) exposed to Leishmania donovani promastigotes. In naive BMM, the parasite failed to induce the phosphorylation of p38 MAPK, c‐Jun N‐terminal kinase (JNK), and extracellular signal‐regulated kinase (ERK)1/2, as well as the degradation of IκB‐α. The use of L. donovani mutants defective in the biosynthesis of lipophosphoglycan revealed that evasion of ERK1/2 activation requires surface expression of the repeating unit moiety of this virulence determinant. In IFN‐γ‐primed BMM, L. donovani promastigotes strongly induced the phosphorylation of p38 MAPK and ERK1/2, and the use of selective inhibitors for ERK (PD98059) and p38 MAPK (SB203580) revealed that both kinases are required for L. donovani‐induced TNF‐α but not NO2– release. Collectively, these data suggest that both p38 MAPK and ERK1/2 pathways participate in some Leishmania‐induced responses in IFN‐γ‐primed BMM. The ability of L. donovani promastigotes to avoid MAPK and NF‐κB activation in naive macrophages may be part of the strategy evolved by this parasite to evade innate immune responses.

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Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans

Cited by 38 publications

References 31 publications

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

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

Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages

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