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An activation-induced IL-15 isoform is a natural antagonist for IL-15 function.

Zhao L, Hu B, Zhang Y, Song Y, Lin D, Liu Y, Mei Y, Sandikin D, Sun W, Zhuang M, Liu H - Sci Rep (2016)

Bottom Line: Here we identified an IL-15 isoform lacking exon-6, IL-15ΔE6, generated by alternative splicing events of activated immune cells, including macrophages and B cells.Furthermore, flow cytometry analysis demonstrated that IL-15ΔE6 expression reduced the percentages of inflammatory T cells in the spleen and spinal cord, and inhibited the infiltration of macrophages to the CNS.Our results demonstrated that IL-15ΔE6 could be induced during immune activation and function as a negative feedback mechanism to dampen IL-15-mediated inflammatory events.

View Article: PubMed Central - PubMed

Affiliation: Institute of Blood and Marrow Transplantation, Cyrus Tang Hematology Center, Department of Hematology, Collaborative Innovation Center of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, P. R. China.

ABSTRACT
Interleukin 15 (IL-15) expression induces the secretion of inflammatory cytokines, inhibits the apoptosis of activated T cells and prolongs the survival of CD8(+) memory T cells. Here we identified an IL-15 isoform lacking exon-6, IL-15ΔE6, generated by alternative splicing events of activated immune cells, including macrophages and B cells. In vitro study showed that IL-15ΔE6 could antagonize IL-15-mediated T cell proliferation. The receptor binding assay revealed that IL-15ΔE6 could bind to IL-15Rα and interfere with the binding between IL-15 and IL-15Rα. Over-expression of IL-15ΔE6 in the murine EAE model ameliorated the EAE symptoms of the mice. The clinical scores were significantly lower in the mice expressing IL-15ΔE6 than the control mice and the mice expressing IL-15. The inflammation and demyelination of the EAE mice expressing IL-15ΔE6 were less severe than the control group. Furthermore, flow cytometry analysis demonstrated that IL-15ΔE6 expression reduced the percentages of inflammatory T cells in the spleen and spinal cord, and inhibited the infiltration of macrophages to the CNS. Our results demonstrated that IL-15ΔE6 could be induced during immune activation and function as a negative feedback mechanism to dampen IL-15-mediated inflammatory events.

No MeSH data available.


Related in: MedlinePlus

Mice expressing IL-15ΔE6 developed less severe EAE compared with control group and IL-15 group.(a) HGT method mediated high levels of IL-15 expression in the EAE mice. The liver sections of the mice received HGT were stained with polyclonal rabbit Ab to murine IL-15 and goat anti-rabbit IgG. Original magnification × 200. (b) EAE was induced in mice three days after HGT of IL-15-MC, IL-15ΔE6-MC vector and MC vehicle plasmid. The clinical scores were evaluated daily in a double blinded fashion. The graph showed the daily average clinical scores (mean ± SD). (c,d) The HE staining of spinal cords and brains from IL-15, IL-15ΔE6 and control mice with EAE. Original magnification × 100. The numbers of infiltrating immune cells were quantified and analyzed. The data shown are the representative of three experiments, each with 5–6 mice per group. *p < 0.05, **p < 0.01, ***p < 0.001.
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f4: Mice expressing IL-15ΔE6 developed less severe EAE compared with control group and IL-15 group.(a) HGT method mediated high levels of IL-15 expression in the EAE mice. The liver sections of the mice received HGT were stained with polyclonal rabbit Ab to murine IL-15 and goat anti-rabbit IgG. Original magnification × 200. (b) EAE was induced in mice three days after HGT of IL-15-MC, IL-15ΔE6-MC vector and MC vehicle plasmid. The clinical scores were evaluated daily in a double blinded fashion. The graph showed the daily average clinical scores (mean ± SD). (c,d) The HE staining of spinal cords and brains from IL-15, IL-15ΔE6 and control mice with EAE. Original magnification × 100. The numbers of infiltrating immune cells were quantified and analyzed. The data shown are the representative of three experiments, each with 5–6 mice per group. *p < 0.05, **p < 0.01, ***p < 0.001.

Mentions: In order to dissect the in vivo function of IL-15ΔE6, we overexpressed IL-15ΔE6 and IL-15 by hydrodynamic gene transfer (HGT) method in a murine EAE model. The IL-15 and IL-15ΔE6 expressions were quite sustainable. Liver tissues from mice that received HGT injection of IL-15 and IL-15ΔE6 plasmids showed a significantly higher and comparable levels of IL-15 detected by antibody that could recognize the common regions of IL-15 and IL-15ΔE6 (Fig. 4a).


An activation-induced IL-15 isoform is a natural antagonist for IL-15 function.

Zhao L, Hu B, Zhang Y, Song Y, Lin D, Liu Y, Mei Y, Sandikin D, Sun W, Zhuang M, Liu H - Sci Rep (2016)

Mice expressing IL-15ΔE6 developed less severe EAE compared with control group and IL-15 group.(a) HGT method mediated high levels of IL-15 expression in the EAE mice. The liver sections of the mice received HGT were stained with polyclonal rabbit Ab to murine IL-15 and goat anti-rabbit IgG. Original magnification × 200. (b) EAE was induced in mice three days after HGT of IL-15-MC, IL-15ΔE6-MC vector and MC vehicle plasmid. The clinical scores were evaluated daily in a double blinded fashion. The graph showed the daily average clinical scores (mean ± SD). (c,d) The HE staining of spinal cords and brains from IL-15, IL-15ΔE6 and control mice with EAE. Original magnification × 100. The numbers of infiltrating immune cells were quantified and analyzed. The data shown are the representative of three experiments, each with 5–6 mice per group. *p < 0.05, **p < 0.01, ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4863161&req=5

f4: Mice expressing IL-15ΔE6 developed less severe EAE compared with control group and IL-15 group.(a) HGT method mediated high levels of IL-15 expression in the EAE mice. The liver sections of the mice received HGT were stained with polyclonal rabbit Ab to murine IL-15 and goat anti-rabbit IgG. Original magnification × 200. (b) EAE was induced in mice three days after HGT of IL-15-MC, IL-15ΔE6-MC vector and MC vehicle plasmid. The clinical scores were evaluated daily in a double blinded fashion. The graph showed the daily average clinical scores (mean ± SD). (c,d) The HE staining of spinal cords and brains from IL-15, IL-15ΔE6 and control mice with EAE. Original magnification × 100. The numbers of infiltrating immune cells were quantified and analyzed. The data shown are the representative of three experiments, each with 5–6 mice per group. *p < 0.05, **p < 0.01, ***p < 0.001.
Mentions: In order to dissect the in vivo function of IL-15ΔE6, we overexpressed IL-15ΔE6 and IL-15 by hydrodynamic gene transfer (HGT) method in a murine EAE model. The IL-15 and IL-15ΔE6 expressions were quite sustainable. Liver tissues from mice that received HGT injection of IL-15 and IL-15ΔE6 plasmids showed a significantly higher and comparable levels of IL-15 detected by antibody that could recognize the common regions of IL-15 and IL-15ΔE6 (Fig. 4a).

Bottom Line: Here we identified an IL-15 isoform lacking exon-6, IL-15ΔE6, generated by alternative splicing events of activated immune cells, including macrophages and B cells.Furthermore, flow cytometry analysis demonstrated that IL-15ΔE6 expression reduced the percentages of inflammatory T cells in the spleen and spinal cord, and inhibited the infiltration of macrophages to the CNS.Our results demonstrated that IL-15ΔE6 could be induced during immune activation and function as a negative feedback mechanism to dampen IL-15-mediated inflammatory events.

View Article: PubMed Central - PubMed

Affiliation: Institute of Blood and Marrow Transplantation, Cyrus Tang Hematology Center, Department of Hematology, Collaborative Innovation Center of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, P. R. China.

ABSTRACT
Interleukin 15 (IL-15) expression induces the secretion of inflammatory cytokines, inhibits the apoptosis of activated T cells and prolongs the survival of CD8(+) memory T cells. Here we identified an IL-15 isoform lacking exon-6, IL-15ΔE6, generated by alternative splicing events of activated immune cells, including macrophages and B cells. In vitro study showed that IL-15ΔE6 could antagonize IL-15-mediated T cell proliferation. The receptor binding assay revealed that IL-15ΔE6 could bind to IL-15Rα and interfere with the binding between IL-15 and IL-15Rα. Over-expression of IL-15ΔE6 in the murine EAE model ameliorated the EAE symptoms of the mice. The clinical scores were significantly lower in the mice expressing IL-15ΔE6 than the control mice and the mice expressing IL-15. The inflammation and demyelination of the EAE mice expressing IL-15ΔE6 were less severe than the control group. Furthermore, flow cytometry analysis demonstrated that IL-15ΔE6 expression reduced the percentages of inflammatory T cells in the spleen and spinal cord, and inhibited the infiltration of macrophages to the CNS. Our results demonstrated that IL-15ΔE6 could be induced during immune activation and function as a negative feedback mechanism to dampen IL-15-mediated inflammatory events.

No MeSH data available.


Related in: MedlinePlus