慢性腎臟疾病(CKD)是一種與糖尿病、肥胖、高血壓和原發性腎臟疾病相關的併發症，會導致嚴重的腎臟損害和失去功能。腎臟纖維化是慢性腎臟疾病的重要病理特徵之一，並會導致腎衰竭。然而腎臟纖維化的機制仍知之甚少。迄今為止，還沒有有效的療法來治療慢性腎臟疾病。因此，首要的目標是要了解慢性腎臟疾病發病機理的機制。介白素24（IL-24），也稱為黑色素瘤分化相關7（mda-7），是屬於IL-10家族的一種細胞激素。IL-24會通過兩種類型的接受體複合物IL20R1 / IL20R2和IL22R1 / IL20R2傳遞下游訊息並進而執行生理功能。在這項研究中，我們目標是在探討IL-24與慢性腎臟疾病之間的關聯。在動物實驗中，我們發現IL-24在單側輸尿管阻塞（UUO）誘導的CKD小鼠的腎臟組織中表現量是降低的。許多促纖維化因子和促發炎性細胞激素也會參與在UUO所誘導的CKD小鼠中。腎小管間質區域會有許多細胞外基質（ECM）異常堆積進而造成腎臟纖維化。因此，我們將IL-24重組蛋白藥物作為保護劑給予UUO小鼠，在動物實驗中(in vivo)發現IL-24可減少細胞外基質堆積於腎臟間質並且降低許多促纖維化因子、促發炎性細胞因子的表達並維護其腎臟功能。在細胞實驗中(in vitro)可以發現，TGF-β會去誘導腎臟上皮細胞、周細胞、巨噬細胞轉變成ACTA2+肌纖維母細胞，IL-24可有效的抑制TGF-β所誘導的細胞轉換。根據以上的結果，我們可得到結論，IL-24是一個有潛力的藥物可治療腎臟纖維化和慢性腎臟疾病。

Chronic kidney disease (CKD) is a syndrome which is associated with diabetes, obesity, hypertension and primary renal disorders and results to severe kidney damage and function. Renal fibrosis is one of the important pathological feature in CKD leading to renal failure. However, the mechanisms of renal fibrosis are still poorly understood. Up to now, there is no effective therapy to treat CKD. Thus, it is important to understand the mechanisms underlying the pathogenesis of CKD. Interleukin-24 (IL-24), also known as melanoma differentiation-associated 7 (MDA-7), is one of the cytokines belonging to the IL-10 family. IL-24 signals through two types of receptor complex: IL20R1/IL20R2 and IL22R1/IL20R2 to perform the biological function. In this study, we aimed to investigate the relationship between IL-24 and CKD. In vivo, we discovered that IL-24 was downregulated in the kidney tissue of unilateral ureteric obstruction (UUO)-induced CKD mice, which was associated with the severity of renal fibrosis. Several profibrotic molecules and pro-inflammatory cytokines play the critical roles in the UUO-induced CKD mice. Excessive and aberrant depositions of extracellular matrix (ECM) protein occurred in both glomeruli and interstitial regions. Thus, we used the recombinant IL-24 protein as an agonist to treat mice with renal fibrosis mice. IL-24 treatment inhibited the expression of several fibrogenic factors, pro-inflammatory cytokines and maintained the kidney function in UUO mice. In vitro, TGF-β induced renal epithelial cell, pericyte, macrophage to become myofibroblast which was inhibited by IL-24. In conclusion, IL-24 is a potential therapeutic drug for the treatment of renal fibrosis in CKD.

1. He, L., et al., AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int, 2017. 92(5): p. 1071-1083.
2. Romagnani, P., et al., Chronic kidney disease. Nat Rev Dis Primers, 2017. 3: p. 17088.
3. Liu, Y., Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol, 2011. 7(12): p. 684-96.
4. Humphreys, B.D., Mechanisms of Renal Fibrosis. Annu Rev Physiol, 2018. 80: p. 309-326.
5. Meng, X.M., D.J. Nikolic-Paterson, and H.Y. Lan, TGF-β: the master regulator of fibrosis. Nat Rev Nephrol, 2016. 12(6): p. 325-38.
6. Ma, T.T. and X.M. Meng, TGF-β/Smad and Renal Fibrosis. Adv Exp Med Biol, 2019. 1165: p. 347-364.
7. Yuan, Q., R.J. Tan, and Y. Liu, Myofibroblast in Kidney Fibrosis: Origin, Activation, and Regulation. Adv Exp Med Biol, 2019. 1165: p. 253-283.
8. Sun, Y.B., et al., The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Differentiation, 2016. 92(3): p. 102-107.
9. Leon, L.R. and B.G. Helwig, Role of endotoxin and cytokines in the systemic inflammatory response to heat injury. Front Biosci (Schol Ed), 2010. 2: p. 916-38.
10. Carrero, J.J., et al., Cytokines, atherogenesis, and hypercatabolism in chronic kidney disease: a dreadful triad. Semin Dial, 2009. 22(4): p. 381-6.
11. Black, L.M., J.M. Lever, and A. Agarwal, Renal Inflammation and Fibrosis: A Double-edged Sword. J Histochem Cytochem, 2019. 67(9): p. 663-681.
12. Borthwick, L.A., T.A. Wynn, and A.J. Fisher, Cytokine mediated tissue fibrosis. Biochim Biophys Acta, 2013. 1832(7): p. 1049-60.
13. Ho, A.S. and K.W. Moore, Interleukin-10 and its receptor. Ther Immunol, 1994. 1(3): p. 173-85.
14. Chadban, S.J., et al., Interleukin-10 is a mesangial cell growth factor in vitro and in vivo. Lab Invest, 1997. 76(5): p. 619-27.
15. Deng, J., et al., Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int, 2001. 60(6): p. 2118-28.
16. Sakai, K., et al., Protective effect and mechanism of IL-10 on renal ischemia–reperfusion injury. Laboratory Investigation, 2019. 99(5): p. 671-683.
17. Mu, W., et al., IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease. J Am Soc Nephrol, 2005. 16(12): p. 3651-60.
18. Fickenscher, H., et al., The interleukin-10 family of cytokines. Trends Immunol, 2002. 23(2): p. 89-96.
19. Zdanov, A., Structural features of the interleukin-10 family of cytokines. Curr Pharm Des, 2004. 10(31): p. 3873-84.
20. Caudell, E.G., et al., The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol, 2002. 168(12): p. 6041-6.
21. Menezes, M.E., et al., MDA-7/IL-24: multifunctional cancer killing cytokine. Advances in experimental medicine and biology, 2014. 818: p. 127-153.
22. Leath, C.A., 3rd, et al., Infectivity enhanced adenoviral-mediated mda-7/IL-24 gene therapy for ovarian carcinoma. Gynecol Oncol, 2004. 94(2): p. 352-62.
23. Bosanquet, D.C., et al., Expression of IL-24 and IL-24 receptors in human wound tissues and the biological implications of IL-24 on keratinocytes. Wound Repair Regen, 2012. 20(6): p. 896-903.
24. Poindexter, N.J., et al., IL-24 is expressed during wound repair and inhibits TGFalpha-induced migration and proliferation of keratinocytes. Exp Dermatol, 2010. 19(8): p. 714-22.
25. Kumari, S., et al., Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice. Immunity, 2013. 39(5): p. 899-911.
26. Sa, S.M., et al., The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol, 2007. 178(4): p. 2229-40.
27. Kragstrup, T.W., et al., The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy. Cytokine, 2008. 41(1): p. 16-23.
28. Andoh, A., et al., Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease. J Immunol, 2009. 183(1): p. 687-95.
29. Fonseca-Camarillo, G., et al., Expression of interleukin (IL)-19 and IL-24 in inflammatory bowel disease patients: a cross-sectional study. Clin Exp Immunol, 2014. 177(1): p. 64-75.
30. Persaud, L., et al., Mechanism of Action and Applications of Interleukin 24 in Immunotherapy. Int J Mol Sci, 2016. 17(6).
31. Wang, M., et al., Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem, 2002. 277(9): p. 7341-7.
32. Yang, H.-C., Y. Zuo, and A.B. Fogo, Models of chronic kidney disease. Drug discovery today. Disease models, 2010. 7(1-2): p. 13-19.
33. Bao, Y.W., et al., Kidney disease models: tools to identify mechanisms and potential therapeutic targets. Zool Res, 2018. 39(2): p. 72-86.
34. Ovadya, Y. and V. Krizhanovsky, A new Twist in kidney fibrosis. Nature Medicine, 2015. 21(9): p. 975-977.
35. Kida, Y. and J.S. Duffield, Pivotal role of pericytes in kidney fibrosis. Clin Exp Pharmacol Physiol, 2011. 38(7): p. 467-73.
36. Kramann, R. and B.D. Humphreys, Kidney pericytes: roles in regeneration and fibrosis. Semin Nephrol, 2014. 34(4): p. 374-83.
37. Wang, N., et al., Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation. Scientific Reports, 2017. 7(1): p. 16914.
38. Meng, X.M., T.S. Mak, and H.Y. Lan, Macrophages in Renal Fibrosis. Adv Exp Med Biol, 2019. 1165: p. 285-303.
39. Tang, P.M.-K., D.J. Nikolic-Paterson, and H.-Y. Lan, Macrophages: versatile players in renal inflammation and fibrosis. Nature Reviews Nephrology, 2019. 15(3): p. 144-158.
40. Mitry, M.A. and J.G. Edwards, Doxorubicin induced heart failure: Phenotype and molecular mechanisms. Int J Cardiol Heart Vasc, 2016. 10: p. 17-24.
41. Octavia, Y., et al., Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol, 2012. 52(6): p. 1213-25.
42. Rea, D., et al., Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research. In Vivo, 2016. 30(3): p. 279-90.
43. Pap, D., et al., Microarray Analysis Reveals Increased Expression of Matrix Metalloproteases and Cytokines of Interleukin-20 Subfamily in the Kidneys of Neonate Rats Underwent Unilateral Ureteral Obstruction: A Potential Role of IL-24 in the Regulation of Inflammation and Tissue Remodeling. Kidney Blood Press Res, 2017. 42(1): p. 16-32.
44. Pap, D., et al., Characterization of IL-19, -20, and -24 in acute and chronic kidney diseases reveals a pro-fibrotic role of IL-24. Journal of Translational Medicine, 2020. 18(1): p. 172.
45. Hofmann, S.R., et al., Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol, 2012. 143(2): p. 116-27.
46. Chang, M.S. and Y.H. Hsu, The role of IL-20 in chronic kidney disease and diabetic nephropathy: Pathogenic and therapeutic implications. J Leukoc Biol, 2018. 104(5): p. 919-923.
47. Hsu, Y.H., et al., Interleukin-19 mediates tissue damage in murine ischemic acute kidney injury. PLoS One, 2013. 8(2): p. e56028.
48. Li, H.H., et al., Interleukin-20 induced cell death in renal epithelial cells and was associated with acute renal failure. Genes Immun, 2008. 9(5): p. 395-404.
49. Wei, C.C., et al., Interleukin-20 targets renal cells and is associated with chronic kidney disease. Biochem Biophys Res Commun, 2008. 374(3): p. 448-53.