Upregulated expression of cytotoxicity-related genes in IFN-γ knockout mice with Schistosoma japonicum infection - PubMed (original) (raw)

Xiaotang Du et al. J Biomed Biotechnol. 2011.

Abstract

It is well accepted that IFN-γ is important to the development of acquired resistance against murine schistosomiasis. However, the in vivo role of this immunoregulatory cytokine in helminth infection needs to be further investigated. In this study, parasite burden and host immune response were observed in IFN-γ knockout mice (IFNg KO) infected with Schistosoma japonicum for 6 weeks. The results suggested that deficiency in IFN-γ led to decreased egg burden in mice, with low schistosome-specific IgG antibody response and enhanced activation of T cells during acute infection. Microarray and qRT-PCR data analyses showed significant upregulation of some cytotoxicity-related genes, including those from the granzyme family, tumor necrosis factor, Fas Ligand, and chemokines, in the spleen cells of IFNg KO mice. Furthermore, CD8+ cells instead of NK cells of IFNg KO mice exhibited increased transcription of cytotoxic genes compared with WT mice. Additionally, Schistosoma japonicum-specific egg antigen immunization also could activate CD8+ T cells to upregulate the expression of cytotoxic genes in IFNg KO mice. Our data suggest that IFN-γ is not always a positive regulator of immune responses. In certain situations, the disruption of IFN-γ signaling may up-regulate the cytotoxic T-cell-mediated immune responses to the parasite.

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Figures

Figure 1

Figure 1

Parasite burden of IFNg KO mice and WT mice (n = 10, resp.) at 6 weeks after-infection with Schistosoma japonicum (compared with WT mice, **P < 0.01). (a) Total worms were recovered by portal perfusion at 6 weeks after-infection. (b) Eggs deposited in the liver were counted after digestion of the liver with 5% KOH. (c) Worm pairs were recovered by portal perfusion at 6 weeks after-infection. (d) Eggs deposited per worm couple in the liver. Data are representative of two independent experiments with the similar results.

Figure 2

Figure 2

Dynamics of SWAP- and SEA-specific IgG antibody levels in IFNg KO and WT mice (n = 10, resp.) according to ELISA of sera harvested at day 0, 3 weeks, and 6 weeks after-infection (compared with WT mice, *P < 0.05, **P < 0.01). Data are representative of two independent experiments with the similar results.

Figure 3

Figure 3

Percentage of CD8+ cells among T cells and NK cells among spleen cells as determined by FACS at 6 weeks after-infection with Schistosoma japonicum (compared with WT mice, *P < 0.05).

Figure 4

Figure 4

Type 1/Type 2 cytokine levels in the supernatant of splenocyte cultures of IFNg KO and WT mice (n = 10, resp.) at 6 weeks after Schistosoma japonicum infection by Bio-Plex detection (compared with WT mice, *P < 0.05, **P < 0.01). Data are representative of two independent experiments with the similar results.

Figure 5

Figure 5

Significantly upregulated pathways with differentially expressed genes in splenocytes, purified CD8+ cells, and NK cells in 6-week _Schistosoma japonicum_-infected IFNg KO mice compared with WT mice based on KEGG and GENEMAP databases. The value of “-LgP” stands for the significance of a particular pathway category.

Figure 6

Figure 6

Relative transcription levels of gzma, gzmb, gzmk, prf1, fasl, ccl5, and klrk1 in splenocytes of _Schistosoma japonicum_-infected IFNg KO and WT mice by real-time PCR. Data were analyzed using the Mann-Whitney test for statistical support (compared with WT mice, *P < 0.05, **P < 0.01).

Figure 7

Figure 7

Expression of gzma, gzmb, gzmk, prf1, fasl and tnfsf9 in purified CD8+ cells from SEA-immunized mice, as measured by qRT-PCR (compared with WT mice, *P < 0.05, **P < 0.01).

Figure 8

Figure 8

Cytotoxicity of NK cells exposed to YAC-1 cells from IFNg KO and WT mice immunized with SEA.

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