High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with Leishmania major are interleukin-4 dependent - PubMed (original) (raw)

High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with Leishmania major are interleukin-4 dependent

Andrea Debus et al. Infect Immun. 2003 Dec.

Abstract

Myeloid differentiation protein 88 (MyD88) is a general adaptor for the signaling cascade through receptors of the Toll/IL-1R family. When infected with Leishmania major parasites, MyD88-deficient mice displayed a dramatically enhanced parasite burden in their tissues similar to that found in susceptible BALB/c mice. In contrast, MyD88 knockout mice did not develop ulcerating lesions despite a lack of interleukin-12 (IL-12) production and a predominant T helper 2 cell response. Blockade of IL-4 produced early (day 1) after infection restored a protective T helper 1 response in MyD88 knockout mice.

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Figures

FIG. 1.

FIG. 1.

Lesion development after infection with L. major. Female BALB/c, C57BL/6, and MyD88-deficient C57BL/6 mice were infected with 2 × 106 stationary-phase promastigotes of L. major in 50 μl of PBS subcutaneously in the right hind footpad. Mice received either 500 μl of PBS (controls) or 1 mg of anti-IL-4 antibody 11B11 in 500 μl of PBS intraperitoneally on day 1 after infection. The data shown represent the mean values and standard error of the mean of the footpad swelling of six mice in one of two similar experiments.

FIG. 2.

FIG. 2.

Humoral immune response in _L. major_-infected mice. The titers of _L. major_-specific IgG1 and IgG2a antibodies (A) and concentrations of total IgE (B) were determined on day 35 after infection. The mean and standard deviation are shown.

FIG. 3.

FIG. 3.

Cytokine secretion by cells from lesion-draining lymph nodes on day 35 after infection. Cells (2 × 106/ml) were stimulated in vitro for 48 h. Concentrations of IL-4 and IFN-γ were determined by ELISA. The mean and standard deviation of three mice per group are shown.

FIG. 4.

FIG. 4.

Expression of cytokine and COX-2 mRNAs in lesion-draining lymph nodes during the course of infection. Total RNA was isolated from the lymph nodes of two mice per group at each time point indicated. After reverse transcription, the concentrations of IL-12p35, p40, IL-4, and COX-2 cDNAs were determined by real-time PCR and normalized for two housekeeping genes. The data shown are the means of four determinations.

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