Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: selective impairment of IL-12 induction inLeishmania -infected cells

Belkaid, Yasmine; Butcher, Barbara A.; Sacks, David L.

doi:10.1002/(sici)1521-4141(199804)28:04<1389::aid-immu1389>3.0.co;2-1

Cited by 130 publications

(105 citation statements)

References 43 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A dynamic balance of effector T lymphocytes and T reg cells is necessary at the site of latent infection [12]. Depletion or neutralization of CD4 + T cells, CD8 + T cells, IFN-c, IL-12 or NO induces parasite expansion [11,12,22,23]. Conversely, treatment with anti-IL-10R [24][25][26] or anti-CD25 [13] antibodies leads to sterile cure and loss of immunity.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

Weigand

Belkaid

et al. 2006

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

The inoculation of live Leishmania major to produce a lesion that heals (leishmanization) is to date the only vaccine against cutaneous leishmaniasis that has proven effective in humans, but it still has an unacceptable frequency of large ulcerating lesions that are slow to heal or, in rare cases, non-healing. We have previously shown that C57BL/6 mice vaccinated intradermally with 10 4 L. major/50 lg CpG oligodeoxynucleotides develop little or no dermal lesions and show early containment of parasite growth in the vaccination site, eliminating safety concerns related to the inoculation of live organisms. The addition of CpG to the live vaccine resulted in early activation of dermal dendritic cells and increased IL-6 production, as well as in a reduction in the accumulation of Foxp3 + CD4 + CD25 + regulatory T (T reg ) cells that naturally occurs in the skin following Leishmania infection. Neutralization of IL-6 caused the development of larger lesions and increased local T reg cell numbers. Transfer of vaccine-primed dendritic cells into IL-6-deficient mice mitigated lesion development, indicating that IL-6 reconstitution limited pathology in the vaccination site.

show abstract

Section: Discussionmentioning

confidence: 99%

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

Weigand

Belkaid

et al. 2006

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…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). Furthermore, L. major and Leishmania donovani metacyclic promastigotes inhibit IL-12 production in murine MP in response to IFN-γ and LPS (Belkaid et al, 1998) and mycobacterial products (Carrera et al, 1996).…”

mentioning

confidence: 97%

“…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).…”

mentioning

confidence: 99%

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

Jayakumar

Widenmaier

et al. 2008

Journal of Parasitology

View full text Add to dashboard Cite

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...

show abstract

“…Hence, control of a Leishmania infection requires activation of macrophages to a microbicidal state. To escape the host immune defense and to survive, Leishmania parasites have developed different strategies and inhibit several macrophage functions, including phagocytosis, nitric oxide generation, interleukin-12 (IL-12) production, and major histocompatibility complex class II expression (7,12).…”

mentioning

confidence: 99%

Leishmania majorAmastigotes Induce p50/c-Rel NF-κΒ Transcription Factor in Human Macrophages: Involvement in Cytokine Synthesis

et al. 2004

View full text Add to dashboard Cite

Invasion of a host by pathogens is frequently associated with activation of nuclear factor kappa B (NF-B), which is implicated in various aspects of immune function required for resistance to infection. However, pathogens may also subdue these mechanisms to secure their survival. Here we describe the effect of Leishmania major infection on NF-B transcription factor activation in both promonocytic human cell line U937 and fresh human monocytes. Infection by L. major amastigotes blocked nuclear translocation of a phorbol-12 myristate-13 acetate (PMA)-induced p50/p65 NF-B complex in PMA-treated differentiated U937 cells and triggered expression of p50-and c-Rel-containing complexes in both U937 cells and fresh human monocytes. These p50/c-Rel complexes, triggered by direct cell-parasite interactions, were detectable within 30 min after the interaction and were transcriptionally active. The NF-〉 inhibitor caffeic acid phenethyl ester inhibited production of both tumor necrosis factor alpha and interleukin-10 (IL-10) induced by Leishmania amastigotes in differentiated U937 cells. Similar results for IL-10 induction were observed with amastigote-infected human monocytes. Our results indicate that L. major amastigotes activate NF-B by specifically inducing p50-and c-Rel-containing complexes which are likely involved in the regulation of cytokine synthesis.

show abstract

Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: selective impairment of IL-12 induction inLeishmania -infected cells

Cited by 130 publications

References 43 publications

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

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

Leishmania majorAmastigotes Induce p50/c-Rel NF-κΒ Transcription Factor in Human Macrophages: Involvement in Cytokine Synthesis

Contact Info

Product

Resources

About