Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways

Lee, Hana; Son, Ye Seul; Lee, Mi-Ok; Ryu, Jea-Woon; Park, Kunhyang; Kwon, Ohman; Jung, Kwang Bo; Kim, Kwangho; Ryu, Tae Young; Baek, Aruem; Kim, Janghwan; Jung, Cho-Rok; Ryu, Choong-Min; Park, Young-Jun; Han, Tae-Su; Kim, Dae-Soo; Cho, Hyun-Soo; Son, Mi-Young

doi:10.7150/thno.41534

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Theranostics 2020; 10(11):5048-5063. doi:10.7150/thno.41534 This issue Cite

Research Paper

Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways

Hana Lee^1,2*, Ye Seul Son^1,2*, Mi-Ok Lee^1,2*, Jea-Woon Ryu¹, Kunhyang Park^1,3, Ohman Kwon¹, Kwang Bo Jung^1,2, Kwangho Kim¹, Tae Young Ryu¹, Aruem Baek¹, Janghwan Kim^1,2, Cho-Rok Jung^1,2, Choong-Min Ryu^1,2, Young-Jun Park^1,2, Tae-Su Han¹, Dae-Soo Kim^1,3✉, Hyun-Soo Cho^1,2✉, Mi-Young Son^1,2✉

1. Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahangno, Yuseong-gu, Daejeon 34141, Republic of Korea;
2. KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea;
3. Department of Biology, Chungnam National University, Daejeon, 34134, South Korea
*Both authors contributed equally to this work.

Citation:

Lee H, Son YS, Lee MO, Ryu JW, Park K, Kwon O, Jung KB, Kim K, Ryu TY, Baek A, Kim J, Jung CR, Ryu CM, Park YJ, Han TS, Kim DS, Cho HS, Son MY. Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways. Theranostics 2020; 10(11):5048-5063. doi:10.7150/thno.41534. https://www.thno.org/v10p5048.htm

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Abstract

Several phase 1/2 clinical trials showed that low-dose interleukin-2 (IL-2) treatment is a safe and effective strategy for the treatment of chronic graft-versus-host disease, hepatitis C virus-induced vasculitis, and type 1 diabetes. Ulcerative colitis (UC) is a chronic inflammatory condition of the colon that lacks satisfactory treatment. In this study, we aimed to determine the effects of low-dose IL-2 as a therapeutic for UC on dextran sulfate sodium (DSS)-induced colitis.

Methods: Mice with DSS-induced colitis were intraperitoneally injected with low-dose IL-2. Survival, body weight, disease activity index, colon length, histopathological score, myeloperoxidase activity and inflammatory cytokine levels as well as intestinal barrier integrity were examined. Differential gene expression after low-dose IL-2 treatment was analyzed by RNA-sequencing.

Results: Low-dose IL-2 significantly improved the symptoms of DSS-induced colitis in mice and attenuated pro-inflammatory cytokine production and immune cell infiltration. The most effective dose range of IL-2 was 16K-32K IU/day. Importantly, low-dose IL-2 was effective in ameliorating the disruption of epithelial barrier integrity in DSS-induced colitis tissues by restoring tight junction proteins and mucin production and suppressing apoptosis. The colon tissue of DSS-induced mice exposed to low-dose IL-2 mimic gene expression patterns in the colons of control mice. Furthermore, we identified the crucial role of the PI3K-AKT pathway in exerting the therapeutic effect of low-dose IL-2.

Conclusions: The results of our study suggest that low-dose IL-2 has therapeutic effects on DSS-induced colitis and potential clinical value in treating UC.

Keywords: ulcerative colitis, interleukin-2, dextran sulfate sodium, PI3K-AKT pathway, RNA-sequencing

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APA

Lee, H., Son, Y.S., Lee, M.O., Ryu, J.W., Park, K., Kwon, O., Jung, K.B., Kim, K., Ryu, T.Y., Baek, A., Kim, J., Jung, C.R., Ryu, C.M., Park, Y.J., Han, T.S., Kim, D.S., Cho, H.S., Son, M.Y. (2020). Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways. Theranostics, 10(11), 5048-5063. https://doi.org/10.7150/thno.41534.

ACS

Lee, H.; Son, Y.S.; Lee, M.O.; Ryu, J.W.; Park, K.; Kwon, O.; Jung, K.B.; Kim, K.; Ryu, T.Y.; Baek, A.; Kim, J.; Jung, C.R.; Ryu, C.M.; Park, Y.J.; Han, T.S.; Kim, D.S.; Cho, H.S.; Son, M.Y. Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways. Theranostics 2020, 10 (11), 5048-5063. DOI: 10.7150/thno.41534.

NLM

CSE

Lee H, Son YS, Lee MO, Ryu JW, Park K, Kwon O, Jung KB, Kim K, Ryu TY, Baek A, Kim J, Jung CR, Ryu CM, Park YJ, Han TS, Kim DS, Cho HS, Son MY. 2020. Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways. Theranostics. 10(11):5048-5063.

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