細胞激素已知為主導及調控體內許多免疫及發炎反應的進行。目前已知介白素-10（interleukin-10, IL-10）家族的成員，包括IL-19，IL-20，IL-22，IL-24及IL-26。對於這些細胞激素的功能研究及其所需透過的受體都已有初步的瞭解，其中，IL-19可以使單核球刺激後產生IL-6和TNF-，並且已知和氣喘有相關；而IL-20被發現可以促進皮膚細胞的增生與分化，在一些皮膚的疾病中扮演重要的角色，如牛皮癬等疾病；此外，IL-24則被發現和黑色素瘤的分化有關，並且會抑制部分癌症細胞的生長；IL-26會促進上皮細胞產生IL-10，但會抑制其產生IL-8。經由先前的研究，我們發現已有部分IL-10家族的成員與癌症有所關連，不僅是先前認為的細胞激素多是和發炎有關的認定，因此我們希望可以利用組織微陣列切片透過免疫組織染色的方法，對於多種組織進行染色，來觀察IL-10家族的成員及其功能性受體在各種組織中的表現情形是如何。由染色結果發現IL-20在組織上的表現具有細胞專一性，在不同組織中的內皮細胞、發炎細胞等均有表現，而IL-20R1的表現大致上與IL-20相似。此外，在胰臟癌組織中外分泌系統的細胞中也發現有IL-20的表現，而且利用RT-PCR，我們也發現在胰臟癌組織中可以偵測到IL-20的表現，然而在正常的胰臟cDNA中卻無法偵測到IL-20的表現。此外，先前的研究報導也指出，同樣為IL-10家族的IL-22也可作用在胰臟細胞中，因此我們想找出是否IL-20在胰臟細胞中也有扮演特定的角色。我們首先在胰臟癌細胞株中，利用RT-PCR同樣可以偵測到IL-20的表現，而IL-20所相對應的功能性受體，介白素-20受體一、IL-20受體二及IL-22受體，也同樣在一些胰臟癌細胞株中有所表現。由於發現在胰臟細胞中不僅表現了IL-20，其功能性受體也多有表現，因此想更進一步的探討，在胰臟細胞中IL-20是否是扮演一個autocrine的角色。另一方面，在幽門桿菌感染所造成的十二指腸潰瘍檢體中，也發現與一般胃炎相較之下，有較多的IL-20與IL-20R1表現，尤其是在固有層細胞中，而胃癌細胞株中IL-20和其相對應功能性受體也都有表現，因此也同樣希望能進一步探討IL-20在胃癌細胞上的生理功能，期望能在控制疾病的進程上有所發展。

　IL-10 family includes IL-10, IL-19, IL-20, IL-22, MDA-7 (IL-24), and AK155 (IL-26). These cytokines share not only structural homology but also receptor subunits and perhaps activities. Receptors for these cytokines belong to the class II cytokine receptor family. All these cytokines require two distinct receptor subunits for signaling. One puzzle surrounding the redundancy in receptor utilization by IL-24, IL-19 and IL-20 is that whether these cytokines induce identical signals downstream, or compete the same receptors for a different biological end-point. Much of this could depend on where and when the cytokines and their receptors are expressed. Thus, it is necessary to analyze the expression patterns of these cytokines and its receptors. Cytokines are involved in various inflammatory diseases such as psoriasis, asthma, atherosclerosis, rheumatoid arthritis (RA) and osteoarthritis (OA), in addition to the critical roles playing in tumor development. To evaluate the association of the expression patterns of these cytokine and its receptors with diseases, we performed immunohistochemical (IHC) staining to analyze protein level of IL-10 family and its receptors in clinical specimen. According the results of tissue microarray, we found that the expression of IL-20 is cell-specific in various tissues. And the expression pattern of IL-20R1 is almost the same as the expression pattern of IL-20. Besides, we also found that IL-20 is expressed in pancreatic acinar cells, which is involved in exocrine system. According to previous study, it is reported that acinar cells of the pancreas are the target of IL-22, another member of IL-10 family, and the receptor subunit of IL-22, IL-22R, is also expressed in the pancreas. The IL-22R is also a subunit of the functional receptor of IL-20, paired with IL-20R2, thus we want to evaluate if IL-20 plays any role in the pancreas. We perform RT-PCR to detect the expression level of the transcripts of IL-20 and its functional receptors in several pancreatic cell lines. We found that not only the IL-20 is expressed in pancreatic cells but also its receptors are expressed. So we want to evaluate that if IL-20 is a role of autocrine in the pancreas. On the other hand, in H. pylori-infected duodenal ulcer, we found the expression level of IL-20 and IL-20R1 is up regulated, especially in lamina propria cells. And we also found that IL-20 and its functional receptors are expressed in gastric tumor cell lines. However, their implication in clinics remains to be further investigated. These studies could provide us new insights in disease pathogenesis and develop potential therapeutic drugs.

1 Aggarwal, S., Xie, M. H., Maruoka, M., Foster, J. and Gurney, A. L.: Acinar cells of the pancreas are a target of interleukin-22. J Interferon Cytokine Res 21 (12): 1047-53, 2001
2 Bazan, J. F.: Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 87 (18): 6934-8, 1990
3 Benjamin, D., Knobloch, T. J. and Dayton, M. A.: Human B-cell interleukin-10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt's lymphoma constitutively secrete large quantities of interleukin-10. Blood 80 (5): 1289-98, 1992
4 Blumberg, H., Conklin, D., Xu, W. F., Grossmann, A., Brender, T., Carollo, S., Eagan, M., Foster, D., Haldeman, B. A., Hammond, A., Haugen, H., Jelinek, L., Kelly, J. D., Madden, K., Maurer, M. F., Parrish-Novak, J., Prunkard, D., Sexson, S., Sprecher, C., Waggie, K., West, J., Whitmore, T. E., Yao, L., Kuechle, M. K., Dale, B. A. and Chandrasekher, Y. A.: Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104 (1): 9-19, 2001
5 Burdin, N., Peronne, C., Banchereau, J. and Rousset, F.: Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med 177 (2): 295-304, 1993
6 Chen, W. Y., Cheng, Y. T., Lei, H. Y., Chang, C. P., Wang, C. W. and Chang, M. S.: IL-24 inhibits the growth of hepatoma cells in vivo. Genes Immun, 2005
7 Cush, J. J., Splawski, J. B., Thomas, R., McFarlin, J. E., Schulze-Koops, H., Davis, L. S., Fujita, K. and Lipsky, P. E.: Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 38 (1): 96-104, 1995
8 de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G. and de Vries, J. E.: Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 174 (5): 1209-20, 1991
9 Dumoutier, L., Leemans, C., Lejeune, D., Kotenko, S. V. and Renauld, J. C.: Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167 (7): 3545-9, 2001
10 Fickenscher, H., Hor, S., Kupers, H., Knappe, A., Wittmann, S. and Sticht, H.: The interleukin-10 family of cytokines. Trends Immunol 23 (2): 89-96, 2002
11 Fortis, C., Foppoli, M., Gianotti, L., Galli, L., Citterio, G., Consogno, G., Gentilini, O. and Braga, M.: Increased interleukin-10 serum levels in patients with solid tumours. Cancer Lett 104 (1): 1-5, 1996
12 Gallagher, G., Dickensheets, H., Eskdale, J., Izotova, L. S., Mirochnitchenko, O. V., Peat, J. D., Vazquez, N., Pestka, S., Donnelly, R. P. and Kotenko, S. V.: Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun 1 (7): 442-50, 2000
13 Itoh, K. and Hirohata, S.: The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 154 (9): 4341-50, 1995
14 Jiang, H., Lin, J. J., Su, Z. Z., Goldstein, N. I. and Fisher, P. B.: Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11 (12): 2477-86, 1995
15 Jiang, H., Su, Z. Z., Lin, J. J., Goldstein, N. I., Young, C. S. and Fisher, P. B.: The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. Proc Natl Acad Sci U S A 93 (17): 9160-5, 1996
16 Kim, J., Modlin, R. L., Moy, R. L., Dubinett, S. M., McHugh, T., Nickoloff, B. J. and Uyemura, K.: IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 155 (4): 2240-7, 1995
17 Knappe, A., Hor, S., Wittmann, S. and Fickenscher, H.: Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J Virol 74 (8): 3881-7, 2000
18 Kunz, M., Henseleit-Walter, U., Sorg, C. and Kolde, G.: Macrophage marker 27E10 on human keratinocytes helps to differentiate discoid lupus erythematosus and Jessner's lymphocytic infiltration of the skin. Eur J Dermatol 9 (2): 107-10, 1999
19 Liao, S. C., Cheng, Y. C., Wang, Y. C., Wang, C. W., Yang, S. M., Yu, C. K., Shieh, C. C., Cheng, K. C., Lee, M. F., Chiang, S. R., Shieh, J. M. and Chang, M. S.: IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 173 (11): 6712-8, 2004
20 Liao, Y. C., Liang, W. G., Chen, F. W., Hsu, J. H., Yang, J. J. and Chang, M. S.: IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha. J Immunol 169 (8): 4288-97, 2002
21 Lindholm, C., Quiding-Jarbrink, M., Lonroth, H., Hamlet, A. and Svennerholm, A. M.: Local cytokine response in Helicobacter pylori-infected subjects. Infect Immun 66 (12): 5964-71, 1998
22 Llorente, L., Zou, W., Levy, Y., Richaud-Patin, Y., Wijdenes, J., Alcocer-Varela, J., Morel-Fourrier, B., Brouet, J. C., Alarcon-Segovia, D., Galanaud, P. and Emilie, D.: Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 181 (3): 839-44, 1995
23 Mhashilkar, A. M., Schrock, R. D., Hindi, M., Liao, J., Sieger, K., Kourouma, F., Zou-Yang, X. H., Onishi, E., Takh, O., Vedvick, T. S., Fanger, G., Stewart, L., Watson, G. J., Snary, D., Fisher, P. B., Saeki, T., Roth, J. A., Ramesh, R. and Chada, S.: Melanoma differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy. Mol Med 7 (4): 271-82, 2001
24 Mocellin, S., Panelli, M. C., Wang, E., Nagorsen, D. and Marincola, F. M.: The dual role of IL-10. Trends Immunol 24 (1): 36-43, 2003
25 Moore, K. W., O'Garra, A., de Waal Malefyt, R., Vieira, P. and Mosmann, T. R.: Interleukin-10. Annu Rev Immunol 11: 165-90, 1993
26 Noach, L. A., Bosma, N. B., Jansen, J., Hoek, F. J., van Deventer, S. J. and Tytgat, G. N.: Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection. Scand J Gastroenterol 29 (5): 425-9, 1994
27 Parrish-Novak, J., Xu, W., Brender, T., Yao, L., Jones, C., West, J., Brandt, C., Jelinek, L., Madden, K., McKernan, P. A., Foster, D. C., Jaspers, S. and Chandrasekher, Y. A.: Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions. J Biol Chem 277 (49): 47517-23, 2002
28 Perez, L., Orte, J. and Brieva, J. A.: Terminal differentiation of spontaneous rheumatoid factor-secreting B cells from rheumatoid arthritis patients depends on endogenous interleukin-10. Arthritis Rheum 38 (12): 1771-6, 1995
29 Ramudo, L., Manso, M. A., Sevillano, S. and de Dios, I.: Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile-pancreatic duct obstruction. J Pathol 206 (1): 9-16, 2005
30 Renauld, J. C.: Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nat Rev Immunol 3 (8): 667-76, 2003
31 Rich, B. E.: IL-20: a new target for the treatment of inflammatory skin disease. Expert Opin Ther Targets 7 (2): 165-74, 2003
32 Saeki, T., Mhashilkar, A., Swanson, X., Zou-Yang, X. H., Sieger, K., Kawabe, S., Branch, C. D., Zumstein, L., Meyn, R. E., Roth, J. A., Chada, S. and Ramesh, R.: Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo. Oncogene 21 (29): 4558-66, 2002
33 Sarkar, D., Su, Z. Z., Lebedeva, I. V., Sauane, M., Gopalkrishnan, R. V., Valerie, K., Dent, P. and Fisher, P. B.: mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc Natl Acad Sci U S A 99 (15): 10054-9, 2002
34 Sheikh, F., Baurin, V. V., Lewis-Antes, A., Shah, N. K., Smirnov, S. V., Anantha, S., Dickensheets, H., Dumoutier, L., Renauld, J. C., Zdanov, A., Donnelly, R. P. and Kotenko, S. V.: Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2. J Immunol 172 (4): 2006-10, 2004
35 Sparano, A., Lathers, D. M., Achille, N., Petruzzelli, G. J. and Young, M. R.: Modulation of Th1 and Th2 cytokine profiles and their association with advanced head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 131 (5): 573-6, 2004
36 Su, Z. Z., Madireddi, M. T., Lin, J. J., Young, C. S., Kitada, S., Reed, J. C., Goldstein, N. I. and Fisher, P. B.: The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci U S A 95 (24): 14400-5, 1998
37 Suzuki, T., Tahara, H., Narula, S., Moore, K. W., Robbins, P. D. and Lotze, M. T.: Viral interleukin 10 (IL-10), the human herpes virus 4 cellular IL-10 homologue, induces local anergy to allogeneic and syngeneic tumors. J Exp Med 182 (2): 477-86, 1995
38 Thoreau, E., Petridou, B., Kelly, P. A., Djiane, J. and Mornon, J. P.: Structural symmetry of the extracellular domain of the cytokine/growth hormone/prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis. FEBS Lett 282 (1): 26-31, 1991
39 Vieira, P., de Waal-Malefyt, R., Dang, M. N., Johnson, K. E., Kastelein, R., Fiorentino, D. F., deVries, J. E., Roncarolo, M. G., Mosmann, T. R. and Moore, K. W.: Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A 88 (4): 1172-6, 1991
40 Wan, W. H., Fortuna, M. B. and Furmanski, P.: A rapid and efficient method for testing immunohistochemical reactivity of monoclonal antibodies against multiple tissue samples simultaneously. J Immunol Methods 103 (1): 121-9, 1987
41 Wanidworanun, C. and Strober, W.: Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol 151 (12): 6853-61, 1993
42 Wolk, K., Kunz, S., Asadullah, K. and Sabat, R.: Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol 168 (11): 5397-402, 2002
43 Xie, M. H., Aggarwal, S., Ho, W. H., Foster, J., Zhang, Z., Stinson, J., Wood, W. I., Goddard, A. D. and Gurney, A. L.: Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem 275 (40): 31335-9, 2000
44 Xu, W., Presnell, S. R., Parrish-Novak, J., Kindsvogel, W., Jaspers, S., Chen, Z., Dillon, S. R., Gao, Z., Gilbert, T., Madden, K., Schlutsmeyer, S., Yao, L., Whitmore, T. E., Chandrasekher, Y., Grant, F. J., Maurer, M., Jelinek, L., Storey, H., Brender, T., Hammond, A., Topouzis, S., Clegg, C. H. and Foster, D. C.: A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc Natl Acad Sci U S A 98 (17): 9511-6, 2001
45 Yssel, H., De Waal Malefyt, R., Roncarolo, M. G., Abrams, J. S., Lahesmaa, R., Spits, H. and de Vries, J. E.: IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. J Immunol 149 (7): 2378-84, 1992
46 Zhang, R., Tan, Z. and Liang, P.: Identification of a novel ligand-receptor pair constitutively activated by ras oncogenes. J Biol Chem 275 (32): 24436-43, 2000