慢性腎臟疾病是目前全球最為關注的重要健康課題，直至現今仍然無法找出一個有效治療腎臟衰竭的方法。介白素十九(IL-19)與介白素二十(IL-20)屬於介白素十的家族成員，它們共用相同的受器複合物介白素二十受器一與介白素二十受器二(IL-20R1/IL-20R2)來進行下游的訊息傳遞。先前研究指出，IL-19與IL-20參與在許多發炎疾病當中，包含類風溼性關節炎、乾癬以及腎衰竭等。既然IL-19與IL-20同時參與了腎臟疾病的致病過程，因此本篇研究想藉此探討IL-20R1之抗體51D是否針對慢性腎臟疾病具有治療的功效。首先在小鼠集尿管細胞中，可以發現51D能夠抑制IL-19所誘發之MCP-1、TGF-β1、α-SMA、collagen I以及collagen III的mRNA表現以及TGF-β1蛋白質的表達，同樣在人類近曲小管上皮細胞也能看到51D抑制IL-20所誘發的TGF-β1產生。單側尿道阻斷(UUO)是最常拿來研究腎纖維化及腎臟疾病的實驗方法，因此利用UUO的方式建立慢性腎臟疾病的動物模式來驗證IL-20R1之抗體51D的治療效果。我們發現經過UUO處理的小鼠，纖維化相關分子TGF-β1、α-SMA、collagen I以及III表現量明顯增加，而注射IL-20R1之抗體51D後確實有抑制其表現的效果。同樣的將IL-20R1之基因剔除鼠處理過UUO後，亦能發現其能降低TGF-β1、α-SMA以及collagen I的表現，此時便更進一步的證實，IL-20R1之抗體具有治療慢性腎臟疾病的潛力，能夠中和IL-19與IL-20所引起的發炎反應。

Chronic kidney disease (CKD) is a worldwide public health problem. Until now, there have been no effective therapies to halt the renal failure. Interleukin-19 (IL-19) and interleukin-20 (IL-20) are the members of interleukin-10 (IL-10) family. They share the receptor complexes IL-20R1/IL-20R2. Previous studies showed that IL-19 and IL-20 are involved in several inflammatory diseases, such as rheumatoid arthritis, psoriasis and renal failure. Therefore, we aimed to study whether anti-IL-20R1 monoclonal antibody (mAb), 51D have a therapeutic potential for CKD. We found that 51D could inhibit the IL-19-induced monocyte chemotactic protein-1 (MCP1), transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen I, collagen III transcripts and TGF-β1 production in mouse collecting tubular epithelial cell (M1). It also inhibited IL-20-induced TGF-β1 transcripts in human proximal tubular epithelial cell (HK2). Unilateral ureteral obstruction (UUO) is a well-described model of renal fibrosis and considered a model of CKD. To determine the in vivo function of anti-IL-20R1 mAb, we generated a CKD animal model of UUO in mice and treated with anti-IL-20R1 mAb. We found a marked increase of renal fibrosis-related molecule TGF-β1、α-SMA、collagen I and III transcripts and TGF-β1 protein in mice after UUO. Anti-IL-20R1 mAb reduced the TGF-β1、α-SMA、collagen I and III expression. In addition, TGF-β1、α-SMA and collagen I were also significantly decreased in IL-20R1 knock-out mice after UUO. These results suggested that anti-IL-20R1 mAb may have a therapeutic potential for CKD by neutralizing the activities of IL-19 and IL-20.

1. Leon, L.R. & Helwig, B.G. Role of endotoxin and cytokines in the systemic inflammatory response to heat injury. Front Biosci (Schol Ed) 2, 916-938 (2010).
2. Carrero, J.J., Park, S.H., Axelsson, J., Lindholm, B. & Stenvinkel, P. Cytokines, atherogenesis, and hypercatabolism in chronic kidney disease: a dreadful triad. Seminars in dialysis 22, 381-386 (2009).
3. Chevalier, R.L., Forbes, M.S. & Thornhill, B.A. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney international 75, 1145-1152 (2009).
4. Bottinger, E.P. & Bitzer, M. TGF-beta signaling in renal disease. Journal of the American Society of Nephrology : JASN 13, 2600-2610 (2002).
5. Yamamura, M. [Overview: cytokine groups and their functions--pathophysiological roles of cytokines in diseases]. Nihon rinsho. Japanese journal of clinical medicine 68 Suppl 7, 7-14 (2010).
6. Zdanov, A. Structural features of the interleukin-10 family of cytokines. Current pharmaceutical design 10, 3873-3884 (2004).
7. Chen, W.Y., Cheng, B.C., Jiang, M.J., Hsieh, M.Y. & Chang, M.S. IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein E-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 26, 2090-2095 (2006).
8. Hsu, Y.H. et al. Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis and rheumatism 54, 2722-2733 (2006).
9. Wei, C.C. et al. IL-20: biological functions and clinical implications. Journal of biomedical science 13, 601-612 (2006).
10. Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9-19 (2001).
11. Hsu, Y.H. & Chang, M.S. Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis. Arthritis and rheumatism 62, 3311-3321 (2010).
12. Leng, R.X., Pan, H.F., Tao, J.H. & Ye, D.Q. IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases. Expert opinion on therapeutic targets 15, 119-126 (2011).
13. Li, H.H. et al. Interleukin-20 targets renal mesangial cells and is associated with lupus nephritis. Clin Immunol 129, 277-285 (2008).
14. Hsu, Y.H. et al. Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. The Journal of experimental medicine 208, 1849-1861 (2011).
15. Li, H.H. et al. Interleukin-20 induced cell death in renal epithelial cells and was associated with acute renal failure. Genes and immunity 9, 395-404 (2008).
16. Commins, S., Steinke, J.W. & Borish, L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. The Journal of allergy and clinical immunology 121, 1108-1111 (2008).
17. Liao, Y.C. et al. IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha. J Immunol 169, 4288-4297 (2002).
18. Jordan, W.J. et al. Human IL-19 regulates immunity through auto-induction of IL-19 and production of IL-10. European journal of immunology 35, 1576-1582 (2005).
19. Liao, S.C. et al. IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 173, 6712-6718 (2004).
20. Hsu, Y.H., Hsieh, P.P. & Chang, M.S. Interleukin-19 blockade attenuates collagen-induced arthritis in rats. Rheumatology (Oxford) 51, 434-442 (2012).
21. Sakurai, N. et al. Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation. Rheumatology (Oxford) 47, 815-820 (2008).
22. Otkjaer, K. et al. The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis. The British journal of dermatology 153, 911-918 (2005).
23. Li, H.H. et al. Interleukin-19 upregulates keratinocyte growth factor and is associated with psoriasis. The British journal of dermatology 153, 591-595 (2005).
24. Parrish-Novak, J. et al. Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions. The Journal of biological chemistry 277, 47517-47523 (2002).
25. Wegenka, U.M. IL-20: biological functions mediated through two types of receptor complexes. Cytokine & growth factor reviews 21, 353-363 (2010).
26. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495-497 (1975).
27. Eddy, A.A., Lopez-Guisa, J.M., Okamura, D.M. & Yamaguchi, I. Investigating mechanisms of chronic kidney disease in mouse models. Pediatr Nephrol 27, 1233-1247 (2012).
28. Hsieh, M.Y. et al. Interleukin-20 promotes angiogenesis in a direct and indirect manner. Genes and immunity 7, 234-242 (2006).
29. Oral, H.B. et al. Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26. European journal of immunology 36, 380-388 (2006).
30. Stenderup, K. et al. Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model. The British journal of dermatology 160, 284-296 (2009).
31. Wei, C.C. & Chang, M.S. Mouse interleukin-20 receptor 1a targets renal epithelial cells and is associated with renal calcium deposition. Genes and immunity 10, 237-247 (2009).
32. Wei, C.C. et al. Interleukin-20 targets renal cells and is associated with chronic kidney disease. Biochemical and biophysical research communications 374, 448-453 (2008).
33. Wu, W.P. et al. A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren. American journal of physiology. Renal physiology 299, F929-941 (2010).