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LPS nephropathy in mice is ameliorated by IL-2 independently of regulatory T cells activity.

Bertelli R, Di Donato A, Cioni M, Grassi F, Ikehata M, Bonanni A, Rastaldi MP, Ghiggeri GM - PLoS ONE (2014)

Bottom Line: Proteinuria was inhibited by co-infusion of human IL-2, with reduction at each phase of the disease (24 -48 and 72 hours) whereas IL-2/anti-IL-2 produced weaker effects.In all mice (wild type and p2rx7⁻/⁻) and irrespective of treatment (IL-2, IL-2/anti-IL-2), LPS was associated with progressive signs of renal pathologic involvement resulting in glomerulosclerosis.In conclusion, IL-2 plays a transient protective effect on proteinuria induced by LPS independent of circulating or tissue Tregs but does not modify the outcome of renal degenerative renal lesions.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Dialysis, Transplantation and Laboratory on Physiopathology of Uremia, Giannina Gaslini Children Hospital, Genoa, Italy.

ABSTRACT
Immunosuppressive regulatory T cells (Tregs) have been hypothesized to exert a protective role in animal models of spontaneous (Buffalo/Mna) and/or drug induced (Adriamycin) nephrotic syndrome. In this study, we thought to define whether Tregs can modify the outcome of LPS nephropathy utilizing IL-2 as inducer of tissue and circulating Tregs. LPS (12 mg/Kg) was given as single shot in C57BL/6, p2rx7⁻/⁻ and Foxp3EGFP; free IL-2 (18.000 U) or, in alternative, IL-2 coupled with JES6-1 mAb (IL-2/anti-IL-2) were injected before LPS. Peripheral and tissue Tregs/total CD4+ cell ratio, urinary parameters and renal histology were evaluated for 15 days. IL-2 administration to wild type mice had no effect on peripheral Tregs number, whereas a significant increase was induced by the IL-2/anti-IL-2 immunocomplex after 5 days. Spleen and lymph nodes Tregs were comparably increased. In p2rx7⁻/⁻ mice, IL-2/anti-IL-2 treatment resulted in increase of peripheral Tregs but did not modify the spleen and lymph nodes quota. LPS induced comparable and transient proteinuria in both wild type and p2rx7⁻/⁻ mice. Proteinuria was inhibited by co-infusion of human IL-2, with reduction at each phase of the disease (24 -48 and 72 hours) whereas IL-2/anti-IL-2 produced weaker effects. In all mice (wild type and p2rx7⁻/⁻) and irrespective of treatment (IL-2, IL-2/anti-IL-2), LPS was associated with progressive signs of renal pathologic involvement resulting in glomerulosclerosis. In conclusion, IL-2 plays a transient protective effect on proteinuria induced by LPS independent of circulating or tissue Tregs but does not modify the outcome of renal degenerative renal lesions.

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Treg level regulation by IL-2 and IL-2/anti-IL-2.Peripheral (A) and spleen/lymph nodes (B) Tregs levels were evaluated at several intervals after IL-2 and IL-2/anti-IL-2 treatment and after LPS in both WT and P2×7−/− mice. In the case of IL-2, determination of circulating and tissue Tregs was done after 7 and 14 days from IL-2 that is the time potentially required to achieve a regulatory effect of the cytokine [21].; Tregs were also determined 3 days after LPS that means 17 days from IL-2 treatment. The time required for a regulatory effect of IL-2/anti-IL-2 is instead 5 days. Treg levels were accordingly determined at this time (i.e. 5 days after IL-2/anti-IL-2) and after 3 days from LPS corresponding to 8 days of treatment. * = p≤0.05, ** = p≤0.005, *** = p≤0.0005.
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pone-0111285-g003: Treg level regulation by IL-2 and IL-2/anti-IL-2.Peripheral (A) and spleen/lymph nodes (B) Tregs levels were evaluated at several intervals after IL-2 and IL-2/anti-IL-2 treatment and after LPS in both WT and P2×7−/− mice. In the case of IL-2, determination of circulating and tissue Tregs was done after 7 and 14 days from IL-2 that is the time potentially required to achieve a regulatory effect of the cytokine [21].; Tregs were also determined 3 days after LPS that means 17 days from IL-2 treatment. The time required for a regulatory effect of IL-2/anti-IL-2 is instead 5 days. Treg levels were accordingly determined at this time (i.e. 5 days after IL-2/anti-IL-2) and after 3 days from LPS corresponding to 8 days of treatment. * = p≤0.05, ** = p≤0.005, *** = p≤0.0005.

Mentions: Urinary albumin levels were evaluated with immune-western after LPS (12 mg/Kg) treatment (24 hrs, 48 hrs and 72 hrs after treatment) in wild C57BL/6 and in P2×7−/− mice. In some cases and in both experimental groups (WT and P2×7−/−) IL-2 (18.000 U) and/or IL-2/anti-IL-2 were infused prior LPS to regulate circulating and tissue Tregs (see Figure 3). * = p≤0.05, ** = p≤0.005, *** = p≤0.0005.


LPS nephropathy in mice is ameliorated by IL-2 independently of regulatory T cells activity.

Bertelli R, Di Donato A, Cioni M, Grassi F, Ikehata M, Bonanni A, Rastaldi MP, Ghiggeri GM - PLoS ONE (2014)

Treg level regulation by IL-2 and IL-2/anti-IL-2.Peripheral (A) and spleen/lymph nodes (B) Tregs levels were evaluated at several intervals after IL-2 and IL-2/anti-IL-2 treatment and after LPS in both WT and P2×7−/− mice. In the case of IL-2, determination of circulating and tissue Tregs was done after 7 and 14 days from IL-2 that is the time potentially required to achieve a regulatory effect of the cytokine [21].; Tregs were also determined 3 days after LPS that means 17 days from IL-2 treatment. The time required for a regulatory effect of IL-2/anti-IL-2 is instead 5 days. Treg levels were accordingly determined at this time (i.e. 5 days after IL-2/anti-IL-2) and after 3 days from LPS corresponding to 8 days of treatment. * = p≤0.05, ** = p≤0.005, *** = p≤0.0005.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4208845&req=5

pone-0111285-g003: Treg level regulation by IL-2 and IL-2/anti-IL-2.Peripheral (A) and spleen/lymph nodes (B) Tregs levels were evaluated at several intervals after IL-2 and IL-2/anti-IL-2 treatment and after LPS in both WT and P2×7−/− mice. In the case of IL-2, determination of circulating and tissue Tregs was done after 7 and 14 days from IL-2 that is the time potentially required to achieve a regulatory effect of the cytokine [21].; Tregs were also determined 3 days after LPS that means 17 days from IL-2 treatment. The time required for a regulatory effect of IL-2/anti-IL-2 is instead 5 days. Treg levels were accordingly determined at this time (i.e. 5 days after IL-2/anti-IL-2) and after 3 days from LPS corresponding to 8 days of treatment. * = p≤0.05, ** = p≤0.005, *** = p≤0.0005.
Mentions: Urinary albumin levels were evaluated with immune-western after LPS (12 mg/Kg) treatment (24 hrs, 48 hrs and 72 hrs after treatment) in wild C57BL/6 and in P2×7−/− mice. In some cases and in both experimental groups (WT and P2×7−/−) IL-2 (18.000 U) and/or IL-2/anti-IL-2 were infused prior LPS to regulate circulating and tissue Tregs (see Figure 3). * = p≤0.05, ** = p≤0.005, *** = p≤0.0005.

Bottom Line: Proteinuria was inhibited by co-infusion of human IL-2, with reduction at each phase of the disease (24 -48 and 72 hours) whereas IL-2/anti-IL-2 produced weaker effects.In all mice (wild type and p2rx7⁻/⁻) and irrespective of treatment (IL-2, IL-2/anti-IL-2), LPS was associated with progressive signs of renal pathologic involvement resulting in glomerulosclerosis.In conclusion, IL-2 plays a transient protective effect on proteinuria induced by LPS independent of circulating or tissue Tregs but does not modify the outcome of renal degenerative renal lesions.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Dialysis, Transplantation and Laboratory on Physiopathology of Uremia, Giannina Gaslini Children Hospital, Genoa, Italy.

ABSTRACT
Immunosuppressive regulatory T cells (Tregs) have been hypothesized to exert a protective role in animal models of spontaneous (Buffalo/Mna) and/or drug induced (Adriamycin) nephrotic syndrome. In this study, we thought to define whether Tregs can modify the outcome of LPS nephropathy utilizing IL-2 as inducer of tissue and circulating Tregs. LPS (12 mg/Kg) was given as single shot in C57BL/6, p2rx7⁻/⁻ and Foxp3EGFP; free IL-2 (18.000 U) or, in alternative, IL-2 coupled with JES6-1 mAb (IL-2/anti-IL-2) were injected before LPS. Peripheral and tissue Tregs/total CD4+ cell ratio, urinary parameters and renal histology were evaluated for 15 days. IL-2 administration to wild type mice had no effect on peripheral Tregs number, whereas a significant increase was induced by the IL-2/anti-IL-2 immunocomplex after 5 days. Spleen and lymph nodes Tregs were comparably increased. In p2rx7⁻/⁻ mice, IL-2/anti-IL-2 treatment resulted in increase of peripheral Tregs but did not modify the spleen and lymph nodes quota. LPS induced comparable and transient proteinuria in both wild type and p2rx7⁻/⁻ mice. Proteinuria was inhibited by co-infusion of human IL-2, with reduction at each phase of the disease (24 -48 and 72 hours) whereas IL-2/anti-IL-2 produced weaker effects. In all mice (wild type and p2rx7⁻/⁻) and irrespective of treatment (IL-2, IL-2/anti-IL-2), LPS was associated with progressive signs of renal pathologic involvement resulting in glomerulosclerosis. In conclusion, IL-2 plays a transient protective effect on proteinuria induced by LPS independent of circulating or tissue Tregs but does not modify the outcome of renal degenerative renal lesions.

Show MeSH
Related in: MedlinePlus