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Endogenous IL-13 plays a crucial role in liver granuloma maturation during Leishmania donovani infection, independent of IL-4Rα-responsive macrophages and neutrophils.

McFarlane E, Carter KC, McKenzie AN, Kaye PM, Brombacher F, Alexander J - J. Infect. Dis. (2011)

Bottom Line: This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels.Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy.Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

View Article: PubMed Central - PubMed

Affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

ABSTRACT
Previous studies comparing interleukin 4 receptor α (IL-4Rα)(-/-) and interleukin 4 (IL-4)(-/-) BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13(-/-) BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L. donovani-infected IL-13(-/-) mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα(-/-) mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

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Effect of recombinant interleukin 13 and lipopolysaccharide stimulation on interleukin 12 production by dendritic cells. Dendritic cells were either (a) incubated for 72 hours with lipopolysaccharide (LPS) alone (100 ng/mL), recombinant interleukin 13 (rIL-13) alone (100 ng/mL), or LPS and rIL-13 together, or (b) preincubated with rIL-13 overnight and then stimulated with LPS for a further 48 hours. Supernatants were frozen at −20°C before analysis for IL-12p40 by enzyme-linked immunosorbent assay. Preincubating with rIL-13 prior to LPS stimulation induced a significant increase in IL-12p40 production by dendritic cells compared with LPS stimulation alone (P < .0021) or incubation with rIL-13 and LPS together (P < .0001). pi = preincubated.
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fig7: Effect of recombinant interleukin 13 and lipopolysaccharide stimulation on interleukin 12 production by dendritic cells. Dendritic cells were either (a) incubated for 72 hours with lipopolysaccharide (LPS) alone (100 ng/mL), recombinant interleukin 13 (rIL-13) alone (100 ng/mL), or LPS and rIL-13 together, or (b) preincubated with rIL-13 overnight and then stimulated with LPS for a further 48 hours. Supernatants were frozen at −20°C before analysis for IL-12p40 by enzyme-linked immunosorbent assay. Preincubating with rIL-13 prior to LPS stimulation induced a significant increase in IL-12p40 production by dendritic cells compared with LPS stimulation alone (P < .0021) or incubation with rIL-13 and LPS together (P < .0001). pi = preincubated.

Mentions: Previous studies have demonstrated that IL-4 can prime dendritic cells for IL-12 production and a protective immune response against Leishmania major [19, 20]. Because IL-13 also signals through the IL-4Rα chain and has similar functions to IL-4, we tested the possibility that IL-13 was also able to instruct dendritic cells for IL-12 production. We preincubated dendritic cells with rIL-13 either prior to or at the same time as LPS stimulation and analyzed the supernatants for IL-12p40 production by ELISA. Preincubation of dendritic cells with rIL-13 induced significantly increased levels of IL-12 production compared with levels from LPS stimulation alone (P < .0021, Figure 7). Indeed, preincubation of dendritic cells with rIL-13 was necessary to induce upregulation of IL-12 production following LPS stimulation because incubation of dendritic cells with rIL-13 and LPS together did not lead to significantly increased IL-12 levels compared with levels produced from LPS stimulation alone (P < .0625, Figure 7).


Endogenous IL-13 plays a crucial role in liver granuloma maturation during Leishmania donovani infection, independent of IL-4Rα-responsive macrophages and neutrophils.

McFarlane E, Carter KC, McKenzie AN, Kaye PM, Brombacher F, Alexander J - J. Infect. Dis. (2011)

Effect of recombinant interleukin 13 and lipopolysaccharide stimulation on interleukin 12 production by dendritic cells. Dendritic cells were either (a) incubated for 72 hours with lipopolysaccharide (LPS) alone (100 ng/mL), recombinant interleukin 13 (rIL-13) alone (100 ng/mL), or LPS and rIL-13 together, or (b) preincubated with rIL-13 overnight and then stimulated with LPS for a further 48 hours. Supernatants were frozen at −20°C before analysis for IL-12p40 by enzyme-linked immunosorbent assay. Preincubating with rIL-13 prior to LPS stimulation induced a significant increase in IL-12p40 production by dendritic cells compared with LPS stimulation alone (P < .0021) or incubation with rIL-13 and LPS together (P < .0001). pi = preincubated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105032&req=5

fig7: Effect of recombinant interleukin 13 and lipopolysaccharide stimulation on interleukin 12 production by dendritic cells. Dendritic cells were either (a) incubated for 72 hours with lipopolysaccharide (LPS) alone (100 ng/mL), recombinant interleukin 13 (rIL-13) alone (100 ng/mL), or LPS and rIL-13 together, or (b) preincubated with rIL-13 overnight and then stimulated with LPS for a further 48 hours. Supernatants were frozen at −20°C before analysis for IL-12p40 by enzyme-linked immunosorbent assay. Preincubating with rIL-13 prior to LPS stimulation induced a significant increase in IL-12p40 production by dendritic cells compared with LPS stimulation alone (P < .0021) or incubation with rIL-13 and LPS together (P < .0001). pi = preincubated.
Mentions: Previous studies have demonstrated that IL-4 can prime dendritic cells for IL-12 production and a protective immune response against Leishmania major [19, 20]. Because IL-13 also signals through the IL-4Rα chain and has similar functions to IL-4, we tested the possibility that IL-13 was also able to instruct dendritic cells for IL-12 production. We preincubated dendritic cells with rIL-13 either prior to or at the same time as LPS stimulation and analyzed the supernatants for IL-12p40 production by ELISA. Preincubation of dendritic cells with rIL-13 induced significantly increased levels of IL-12 production compared with levels from LPS stimulation alone (P < .0021, Figure 7). Indeed, preincubation of dendritic cells with rIL-13 was necessary to induce upregulation of IL-12 production following LPS stimulation because incubation of dendritic cells with rIL-13 and LPS together did not lead to significantly increased IL-12 levels compared with levels produced from LPS stimulation alone (P < .0625, Figure 7).

Bottom Line: This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels.Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy.Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

View Article: PubMed Central - PubMed

Affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

ABSTRACT
Previous studies comparing interleukin 4 receptor α (IL-4Rα)(-/-) and interleukin 4 (IL-4)(-/-) BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13(-/-) BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L. donovani-infected IL-13(-/-) mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα(-/-) mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.

Show MeSH
Related in: MedlinePlus