IL233, A novel IL-2 and IL-33 hybrid cytokine, ameliorates renal injury

Marta E. Stremska, Sheethal Jose, Vikram Sabapathy, Liping Huang, Amandeep Bajwa, Gilbert R. Kinsey, Poonam R. Sharma, Saleh Mohammad, Diane L. Rosin, Mark D. Okusa, Rahul Sharma

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) protect the kidney during AKI.We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4+ T cells, thuswe hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone. Accordingly, we generated a novel hybrid cytokine (IL233) bearing the activities of IL-2 and IL-33 for efficient targeting to Tregs. IL233 treatment increased the number of Tregs in blood and spleen and prevented IRI more efficiently than a mixture of IL-2 and IL-33. Injection of IL233 also increased the numbers of Tregs in renal compartments. Moreover, IL233-treated mice had fewer splenic Tregs and more Tregs in kidneys after IRI. In vitro, splenic Tregs from IL233-treated mice suppressed CD4+ T cell proliferation better than Tregs fromsaline-treated controls. IL233 treatment also improved the ability of isolated Tregs to inhibit IRI in adoptive transfer experiments and protectedmice fromcisplatin- and doxorubicin-induced nephrotoxic injury. Finally, treatmentwith IL233 increased the proportion of ST2-bearing innate lymphoid cells (ILC2) in blood and kidneys, and adoptive transfer of ILC2 also protectedmice fromIRI. Thus, the novel IL233 hybrid cytokine, which utilizes the cooperation of IL-2 and IL-33 to enhance Treg- and ILC2-mediated protection from AKI, bears strong therapeutic potential.

Original languageEnglish (US)
Pages (from-to)2681-2693
Number of pages13
JournalJournal of the American Society of Nephrology
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2017

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Interleukin-2
Cytokines
Reperfusion Injury
Kidney
Wounds and Injuries
Adoptive Transfer
T-Lymphocytes
Regulatory T-Lymphocytes
Doxorubicin
Interleukin-33
Homeostasis
Up-Regulation
Therapeutics
Spleen
Cell Proliferation
Lymphocytes
Injections

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Stremska, M. E., Jose, S., Sabapathy, V., Huang, L., Bajwa, A., Kinsey, G. R., ... Sharma, R. (2017). IL233, A novel IL-2 and IL-33 hybrid cytokine, ameliorates renal injury. Journal of the American Society of Nephrology, 28(9), 2681-2693. https://doi.org/10.1681/ASN.2016121272

IL233, A novel IL-2 and IL-33 hybrid cytokine, ameliorates renal injury. / Stremska, Marta E.; Jose, Sheethal; Sabapathy, Vikram; Huang, Liping; Bajwa, Amandeep; Kinsey, Gilbert R.; Sharma, Poonam R.; Mohammad, Saleh; Rosin, Diane L.; Okusa, Mark D.; Sharma, Rahul.

In: Journal of the American Society of Nephrology, Vol. 28, No. 9, 01.09.2017, p. 2681-2693.

Research output: Contribution to journalArticle

Stremska, ME, Jose, S, Sabapathy, V, Huang, L, Bajwa, A, Kinsey, GR, Sharma, PR, Mohammad, S, Rosin, DL, Okusa, MD & Sharma, R 2017, 'IL233, A novel IL-2 and IL-33 hybrid cytokine, ameliorates renal injury', Journal of the American Society of Nephrology, vol. 28, no. 9, pp. 2681-2693. https://doi.org/10.1681/ASN.2016121272
Stremska, Marta E. ; Jose, Sheethal ; Sabapathy, Vikram ; Huang, Liping ; Bajwa, Amandeep ; Kinsey, Gilbert R. ; Sharma, Poonam R. ; Mohammad, Saleh ; Rosin, Diane L. ; Okusa, Mark D. ; Sharma, Rahul. / IL233, A novel IL-2 and IL-33 hybrid cytokine, ameliorates renal injury. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 9. pp. 2681-2693.
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abstract = "CD4+Foxp3+ regulatory T cells (Tregs) protect the kidney during AKI.We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4+ T cells, thuswe hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone. Accordingly, we generated a novel hybrid cytokine (IL233) bearing the activities of IL-2 and IL-33 for efficient targeting to Tregs. IL233 treatment increased the number of Tregs in blood and spleen and prevented IRI more efficiently than a mixture of IL-2 and IL-33. Injection of IL233 also increased the numbers of Tregs in renal compartments. Moreover, IL233-treated mice had fewer splenic Tregs and more Tregs in kidneys after IRI. In vitro, splenic Tregs from IL233-treated mice suppressed CD4+ T cell proliferation better than Tregs fromsaline-treated controls. IL233 treatment also improved the ability of isolated Tregs to inhibit IRI in adoptive transfer experiments and protectedmice fromcisplatin- and doxorubicin-induced nephrotoxic injury. Finally, treatmentwith IL233 increased the proportion of ST2-bearing innate lymphoid cells (ILC2) in blood and kidneys, and adoptive transfer of ILC2 also protectedmice fromIRI. Thus, the novel IL233 hybrid cytokine, which utilizes the cooperation of IL-2 and IL-33 to enhance Treg- and ILC2-mediated protection from AKI, bears strong therapeutic potential.",
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