化療所引起的腸道黏膜炎其主要症狀為體重下降、腹瀉、腸道損傷發炎。介白素-19和介白素-20是介白素-10家族成員中的一員，由文獻已知介白素-19和介白素-20皆參與在許多發炎性相關的疾病當中。我們以5-FU這個常見的化療藥物去誘導腸道黏膜炎小鼠動物模式，首先我們利用anti-IL-20單株抗體7E作為治療化療藥物5-FU引起的腸道黏膜炎的小鼠，但7E卻沒有任何的保護效果，因此我們進一步利用IL-20R1剔除小鼠將IL-20的接受器剔除，發現在誘導成腸道黏膜炎時，IL-20R1剔除小鼠可以保護大腸不受到化療藥物的損傷、發炎基因表現量也降低，細胞凋亡的情形在IL-20R1剔除小鼠中也有明顯減緩的情況。接下來我們利用anti-IL-20R1單株抗體51D作為藥物治療5-FU引起的腸道黏膜炎的小鼠，與IL-20R1剔除小鼠的結果一致，51D也可以保護大腸的組織型態、減少發炎基因的表現以及減緩細胞凋亡的情形，結果顯示阻斷IL-20R1可以改善化療所引起的腸道黏膜炎，因此我們認為可能不是IL-20參與在其中而是同樣會接上IL-20R1的IL-19參與在化療所引起的腸道黏膜炎當中。接下來我們利用抗IL-19抗體1BB1作為藥物治療5-FU引起的腸道黏膜炎的大鼠，與51D的結果相似，1BB1可以降低大腸發炎基因的表現，並且可以減少化療藥物對於大腸組織的損傷。因此我們實驗結果顯示IL-19的確作為一個促發炎反應的細胞激素參與在化療引起的腸道黏膜炎當中，並且1BB1阻斷IL-19可能是改善化療引起的腸道黏膜炎的治療藥物。

Chemotherapy-induced intestinal mucositis is a common side effect and a major cause of morbidity and mortality in cancer patients. 5-Fluorouracil (5-FU) is an anticancer drug that is widely used in the treatment of gastrointestinal malignancies. About 50- 80% of patients who received 5-FU resulted in severe mucositis indicated by diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cytokines, such as interleukin-1(IL-1), IL-6 and TNF. IL-20 is a proinflammatory cytokine, which can induce IL-1, IL-6 and TNF in different types of cells. Therefore, we were aimed to investigate the association of IL-20 with chemotherapy-induced intestinal mucositis. We chose the well-established 5-FU-induced intestinal mucositis as the animal disease model. The expression of IL-20 was elevated in colonic tissue of 5-FU-treated mice compared to healthy control analyzed by RT-qPCR and Immunohistochemistry (IHC). However, anti-IL-20 monoclonal antibody 7E did not suppress the symptom of mucositis. In addition, apoptosis in colon was attenuated in IL-20R1KO mice and anti-IL-20R1 antibody(51D)-treated mice. IL-20 R1KO mice and 51D-treated mice also protected the contents of mucin and colon morphology from 5-FU-treated injuries. Thus, we hypothesized that IL-19, which is a proinflammatory cytokine binding to IL-20R1, may be involved in 5-FU-induced intestinal mucositis. We further used anti-IL-19 antibody (1BB1) in rat model to confirm our hypothesis. 1BB1 treatment reduced colon inflammation by inhibiting the inflammatory cytokines. Furthermore, submucosal edema in colon was attenuated in 1BB1-treated rat. Our data indicated that IL-19 was involved in the pathogenesis of 5-FU-induced intestinal mucositis. Therefore, IL-19 antagonist may be a potential therapeutic.

1. Keefe, D.M., Intestinal mucositis: mechanisms and management. Curr Opin Oncol, 2007. 19(4): p. 323-7.
2. Peterson, D.E., et al., Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol, 2015. 26 Suppl 5: p. v139-51.
3. Sonis, S.T., The pathobiology of mucositis. Nat Rev Cancer, 2004. 4(4): p. 277-84.
4. Jenkins, T.A., Perinatal complications and schizophrenia: involvement of the immune system. Front Neurosci, 2013. 7: p. 110.
5. Hombach, A.A. and H. Abken, Targeting two co-operating cytokines efficiently shapes immune responses. Oncoimmunology, 2013. 2(3): p. e23205.
6. Osburn, W.O., et al., Anti-inflammatory cytokines, pro-fibrogenic chemokines and persistence of acute HCV infection. J Viral Hepat, 2013. 20(6): p. 404-13.
7. Chen, Y., et al., 1,3-beta-glucan affects the balance of Th1/Th2 cytokines by promoting secretion of anti-inflammatory cytokines in vitro. Mol Med Rep, 2013. 8(2): p. 708-12.
8. Bossaller, L. and A. Rothe, Monoclonal antibody treatments for rheumatoid arthritis. Expert Opin Biol Ther, 2013. 13(9): p. 1257-72.
9. Halwani, R., et al., A novel anti-IL4Ralpha nanoparticle efficiently controls lung inflammation during asthma. Exp Mol Med, 2016. 48(10): p. e262.
10. Mizutani, H., et al., Lipopolysaccharide of Aggregatibacter actinomycetemcomitans up-regulates inflammatory cytokines, prostaglandin E2 synthesis and osteoclast formation in interleukin-1 receptor antagonistdeficient mice. J Periodontal Res, 2013. 48(6): p. 748-56.
11. Jordan, W.J., et al., Human IL-19 regulates immunity through auto-induction of IL-19 and production of IL-10. Eur J Immunol, 2005. 35(5): p. 1576-82.
12. 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, 2002. 169(8): p. 4288-97.
13. Kunz, S., et al., Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp Dermatol, 2006. 15(12): p. 991-1004.
14. Leng, R.X., et al., IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases. Expert Opin Ther Targets, 2011. 15(2): p. 119-26.
15. 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. Eur J Immunol, 2006. 36(2): p. 380-8.
16. Commins, S., J.W. Steinke, and L. Borish, The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol, 2008. 121(5): p. 1108-11.
17. Steinert, A., et al., The Stimulation of Macrophages with TLR Ligands Supports Increased IL-19 Expression in Inflammatory Bowel Disease Patients and in Colitis Models. J Immunol, 2017. 199(7): p. 2570-2584.
18. Niess, J.H., P. Hruz, and T. Kaymak, The Interleukin-20 Cytokines in Intestinal Diseases. Front Immunol, 2018. 9: p. 1373.
19. Blumberg, H., et al., Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell, 2001. 104(1): p. 9-19.
20. Hsu, Y.H. and M.S. Chang, The therapeutic potential of anti-interleukin-20 monoclonal antibody. Cell Transplant, 2014. 23(4-5): p. 631-9.
21. Zdanov, A., Structural features of the interleukin-10 family of cytokines. Curr Pharm Des, 2004. 10(31): p. 3873-84.
22. Rutz, S., X. Wang, and W. Ouyang, The IL-20 subfamily of cytokines--from host defence to tissue homeostasis. Nat Rev Immunol, 2014. 14(12): p. 783- 95.
23. Sabat, R., et al., Immunopathogenesis of psoriasis. Exp Dermatol, 2007. 16(10): p. 779-98.
24. Stenderup, K., et al., Interleukin-20 as a target in psoriasis treatment. Ann N Y Acad Sci, 2007. 1110: p. 368-81.
25. Michalak-Stoma, A., et al., Cytokine network in psoriasis revisited. Eur Cytokine Netw, 2011. 22(4): p. 160-8.
26. Kleemann, R., S. Zadelaar, and T. Kooistra, Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res, 2008. 79(3): p. 360- 76.
27. Brennan, F. and J. Beech, Update on cytokines in rheumatoid arthritis. Curr Opin Rheumatol, 2007. 19(3): p. 296-301.
28. Soares, P.M., et al., Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution. Cancer Chemother Pharmacol, 2008. 63(1): p. 91-8.
29. Logan, R.M., et al., Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemother Pharmacol, 2009. 63(2): p. 239-51.
30. Ribeiro, R.A., et al., Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol, 2016. 78(5): p. 881-893.
31. Wu, Z.Q., et al., Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice. Cancer Chemother Pharmacol, 2011. 68(1): p. 87-96.
32. Inomata, A., I. Horii, and K. Suzuki, 5-Fluorouracil-induced intestinal toxicity: what determines the severity of damage to murine intestinal crypt epithelia? Toxicol Lett, 2002. 133(2-3): p. 231-40.
33. Nita, M.E., et al., 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer, 1998. 78(8): p. 986-92.
34. Bowen, J.M., et al., Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans. Pathology, 2005. 37(1): p. 56-62.
35. Barnes, P.J. and M. Karin, Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med, 1997. 336(15): p. 1066-71.
36. Bonizzi, G. and M. Karin, The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol, 2004. 25(6): p. 280-8.
37. Chang, C.T., et al., 5-Fluorouracil induced intestinal mucositis via nuclear factor-kappaB activation by transcriptomic analysis and in vivo bioluminescence imaging. PLoS One, 2012. 7(3): p. e31808.
38. Mahr, S., et al., IL-1beta-induced apoptosis in rat gastric enterochromaffinlike cells is mediated by iNOS, NF-kappaB, and Bax protein. Gastroenterology, 2000. 118(3): p. 515-24.
39. Yip, K.H., et al., Induction of nitric oxide synthases in primary human cultured mast cells by IgE and proinflammatory cytokines. Int Immunopharmacol, 2008. 8(5): p. 764-8.
40. Lima-Junior, R.C., et al., Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation. Cancer Chemother Pharmacol, 2012. 69(4): p. 931- 42.
41. Li, H.L., et al., Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis. Front Cell Infect Microbiol, 2017. 7: p. 455.