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PMID:19047410

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Citation

Kamda, JD and Singer, SM (2009) Phosphoinositide 3-kinase-dependent inhibition of dendritic cell interleukin-12 production by Giardia lamblia. Infect. Immun. 77:685-93

Abstract

Dendritic cell interactions with pathogenic microbes initiate and direct the development of subsequent adaptive responses. The protozoan pathogen Giardia lamblia infects the mammalian small intestine, leading to nutrient malabsorption and diarrhea but rarely causing inflammation. In order to begin to understand how the innate immune system responds to this parasite and shapes the eventual adaptive response, we examined the interaction between parasites and murine bone marrow-derived dendritic cells (DCs). DCs incubated with live parasites or parasite extracts displayed enhanced levels of CD40. The expression of CD80 and CD86 also increased, but less than was seen with lipopolysaccharide-activated DCs. Small amounts of interleukin-6 (IL-6) and tumor necrosis factor alpha were secreted by these DCs, whereas no IL-10 or IL-12 could be detected. Coincubation of DCs with parasite extracts along with known Toll-like receptor (TLR) ligands resulted in enhanced secretion of IL-10 and reduced secretion of IL-12. The levels of major histocompatibility complex class II, CD80, and CD86 were also reduced compared to DCs stimulated with TLR ligands alone. Finally, studies with an extracellular signal-regulated kinase 1/2 pathway inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and anti-IL-10 receptor antibody revealed that the PI3K pathway is the dominant mechanism of inhibition in DCs incubated with both lipopolysaccharide and Giardia. These data suggest that this parasite actively interferes with host innate immunity, resulting in an immune response able to control the infection but devoid of strong inflammatory signals.

Links

PubMed PMC2632045 Online version:10.1128/IAI.00718-08

Keywords

Androstadienes/pharmacology; Animals; Dendritic Cells/drug effects; Dendritic Cells/metabolism; Dimethyl Sulfoxide/pharmacology; Dose-Response Relationship, Drug; Female; Giardia lamblia/physiology; Interleukin-10/metabolism; Interleukin-12/metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases/metabolism; Toll-Like Receptors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:IL10

acts_upstream_of_or_within

GO:0042832: defense response to protozoan

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL10

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MP2K1

acts_upstream_of_or_within

GO:0006468: protein phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1346867

P

Seeded From UniProt

complete

MOUSE:CD86

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL12A

acts_upstream_of_or_within

GO:0042832: defense response to protozoan

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL12A

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MK01

acts_upstream_of_or_within

GO:0070371: ERK1 and ERK2 cascade

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1346859

P

Seeded From UniProt

complete

MOUSE:CD80

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MK03

acts_upstream_of_or_within

GO:0070371: ERK1 and ERK2 cascade

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1346858

P

Seeded From UniProt

complete

MOUSE:MP2K2

acts_upstream_of_or_within

GO:0006468: protein phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1346866

P

Seeded From UniProt

complete

MOUSE:TLR9

acts_upstream_of_or_within

GO:0002730: regulation of dendritic cell cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TNR5

acts_upstream_of_or_within

GO:0042832: defense response to protozoan

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TNFA

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL6

acts_upstream_of_or_within

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TLR3

acts_upstream_of_or_within

GO:0002730: regulation of dendritic cell cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TLR4

acts_upstream_of_or_within

GO:0002730: regulation of dendritic cell cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TLR2

acts_upstream_of_or_within

GO:0002730: regulation of dendritic cell cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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