細胞激素(cytokines)在調節免疫反應及淋巴細胞的生長分化上扮演重要角色，介白素10 (interleukin-10，IL-10)是一多功能的細胞激素，已知對於許多不同的細胞會有免疫刺激或免疫抑制的不同作用。介白素22 (interleukin-22，IL-22)是IL-10家族之一的成員，為具有179個胺基酸的蛋白質，在胺基酸序列上和IL-10有25% 相似性，且其二級結構類似。IL-22是以IL-9刺激老鼠的T淋巴細胞之後，利用cDNA subtraction方法而被發現的新基因，目前已知的生物功能包括，它能使肝臟細胞與其細胞株(HepG2)產生急性期反應物(acute-phase reactants)，使脾臟的腺泡細胞(acinar cell)產生脾臟炎相關蛋白質，因此推測它的功能是和發炎反應相關。IL-22會和細胞膜上的接受器綜合體，歸類為第二細胞激素接受器家族的IL-10R2和 IL-22R1，結合後所進行的訊息傳遞會使轉錄作用信號傳遞活化因子3(STAT-3)磷酸化，但若是和另一分泌性接受器，又稱為IL-22結合蛋白(IL-22 binding protein)，結合後會阻礙其和接受器綜合體結合，使STAT-3無法磷酸化。
為了更進一步了解IL-22的生物功能以及和結合蛋白之間的作用，於是分別純化由原核大腸桿菌系統、真核酵母菌系統所表現的IL-22和其結合蛋白，實驗證實所純化出的結合蛋白可以抑制IL-22的功能使細胞不具有STAT-3磷酸化作用，也將所純化的IL-22分別作用於T細胞、B細胞、單核細胞觀察並分析結果，由實驗結果發現IL-22可促使B細胞增生; 使單核細胞產生介白素6 (IL-6) 和腫瘤壞死因子 (TNF-) 這兩種和發炎反應相關的細胞激素，且當加入結合蛋白或單株抗體可抑制IL-22刺激單核細胞產生IL-6與TNF-的作用; 人類的IL-22和老鼠的IL-22都可以促使人類及老鼠的單核細胞產生IL-6和TNF-; 而身體中還有兩種不同形式的IL-22結合蛋白存在，命名為IL-22BPL 和IL-22BPS，對於IL-22有不同程度的抑制作用; 由於IL-22會影響發炎反應，所以在某些組織所存在的結合蛋白，可調控局部的發炎反應。
IL-22與IL-10家族成員: IL-10、IL-19、IL-20和IL-26之間對單核細胞的影響，可利用個別加入或合併IL-22與其他不同的細胞激素來處理單核細胞，由結果可知IL-19、IL-20和IL-22單獨作用於單核細胞都可使其產生IL-6 和TNF-，合併IL-22和IL-19或IL-20有相加作用，IL-10可完全抑制IL-22的作用，而IL-26則有部分抑制作用，綜合以上實驗結果可知，IL-22和IL-19及IL-20具有類似功能且有相加作用，而結合蛋白則在調控IL-22發炎反應上扮演重要角色。

Cytokines play important roles in the regulation of immune response and lymphocyte development. Interleukin-10 is a pleiotropic cytokine that can exert either immunostimulatory or immunosuppressive effects on a variety of cell types. Interleukin-22, a member of IL-10 family, encodes a protein of 179 amino acids that shares 25% identity with inteleukin-10, and structural similarity with IL-10. IL-22 is originally identified as a gene induced by IL-9 in murine T lymphocytes. The biological activities of IL-22 known thus far are the induction of acute-phase reactants in liver and hepatoma cells as well as induction of pancreatitis-associated protein (PAP1) in pancreatic acinar cells, suggesting its role in inflammatory response. IL-22 binds at the cell surface to a receptor complex belonging to the class II cytokine receptor family: IL-10R2 and IL-22R1. Signaling through the receptor complex induces the phosphorylation of STAT3. A soluble receptor designed CRF class II member 10 (CRF2-10) or IL-22BP binds to IL-22 and prevents its interaction with the functional IL-22R complex, and thus blocks the STAT3 activation.
To further evaluate the IL-22 biological function and the interaction of IL-22 and its binding protein; we purified IL-22 and IL-22BP recombinant proteins expressed in the prokaryotic E. coli system and yeast Pichia system. We demonstrated that IL-22BP can neutralize STAT3 activation in hepatoma cell line (HepG2) stimulated with IL-22. In order to explore other biological functions of IL-22, we treated T cells, B cells, and monocytes with IL-22 and analyzed the results. IL-22 induced B cells proliferation. Treatment of monocytes with IL-22 induced dose-dependent production of IL-6 and TNF-, and that was blocked by IL-22BP and IL-22 monoclonal Ab. Both hIL-22 and mIL-22 induced production of IL-6 and TNF- in human and mouse monocytes. Two alternatively splice variants, IL-22BPL and IL-22BPS can neutralize IL-22 activity in different level. Because IL-22 was implicated in inflammation, the expression of IL-22BP in certain tissues perhaps modulated local inflammation.
The relationships between IL-22 and other members of IL-10 family: IL-10, IL19, IL-20, and IL-26 were analyzed by treating monocytes with combinations of different cytokines. IL-19, IL-20, IL-22 separately induced the production of IL-6 and TNF-. Moreover, IL-22 induced the production of IL-6 and TNF-, which was slightly enhanced by the addition of IL-19 and IL-20. IL-10 completely inhibited the induction of IL-6 and TNF- by IL-22. IL-26 partially inhibited the IL-22 activity. These results showed that IL-22, IL-19 and IL-20 had synergistic effect, and IL-22BP might play an important role as an IL-22 antagonist in the regulation of inflammatory response.

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: 1047-1053, 2001.

2. Blumberg H, C.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: 9-19, 2001.

3. Buttke, T.M and Sandstrom, P. A. Redox regulation of programmed cell death in lymphocytes. Free Radic. Res. 22: 389-397, 1995.

4. de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. and de Vries, J. Interleukin-10 inhibits cytokin synthesis by human monocytes: an autoregulatory role of IL-10 producted by monocyytes. J. Exp. Med. 174: 1209-1220, 1991.

5. Dobmeyer, T.S., Findhammer, S., Dobmeyer, J.M., Klein, S.A., Raffel, B., Hoelzer, D., Helm, E.B., Kabelitz, D. and Rossol, R. Ex vivo indction of apoptosis in lymphocytes is mediated by oxidative stress: role for lymphocyte loss in HIV infection. Free Radic. Biol. Med. 22: 775-785, 1997.

6. Dokka, S., Shi, X., Leonard, S., Wang, L., Castranova, V. and Rojanasakul, Y. Interleukin-10-mediated inhibition of freeradical generation in macropgages. Am. J. Physiol. Lung Cell. Mol. Physiol. 280: L1196-L1202, 2001.

7. Domoutier, L., Roost, E.V., Ameye, G., Michaux, L. and Renauld, J.C.IL-TIF/IL-22: genomic organization and mapping of the huamn and mouse genes. Genes and Immunity. 1:488-494, 2000.

8. Dumoutier, L., Leemans, C., Lejeune, D., Kotenko, S.V. and Renauld, J.C. Cutting edge: STAT activation by IL-19, IL-20 and mda-24 through IL-20 receptor complexes of two types. J. Immunol. 167: 3545-3549, 2001.

9. Dumoutier, L., Lejeune, D., Colau, D. and Renauld, J.C. Cloning and characterization of L-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J. Immunol. 166: 7090-7095, 2001.

10. Dumoutier, L., Louahed, J. and Renauld, J.C. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J. Immunol. 164: 1814-1819, 2000a.

11. Dumoutier, L., Van Roost, E., Colau, D. and Renauld, J.C. Human IL-TIF: molecular cloning and functional characterization as a hepatocyte stimulating factor. Proc. Natl. Acad. Sci. USA 97: 10144-10149, 2000b.

12. Ellerhorst, J.A., Prieto, V.G., Ekmekcioglu, S., Broemeling, L., Yekell, S., Chada, S. and Grimm, E.A. Loss of MDA-7 expression with progression of melanoma. J. Clin. Oncol. 20, 1069-1074, 2002.

13. Fedyk, T.M. and Phipps, R.P. Reactive oxygen species and not lipoxygenase products are required for mouse B-lymphocyte activation and differentiation. Int. J. Immunopharmacol. 16:533-546, 1994.

14. Fickenscher, H., Hor, S., Kuper, H., knappe, A., Wittmann, S. and Sticht, H. The interleukin-10 family of cytokines. TRENDS in Immunology. 23: 89-96, 2002.

15. Gallagher G, D.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: 442-450, 2000.

16. Gesser, B., Leffers, H., Jinquan, T., Vestergaard, C., Kirstein, N., Sindet-Pedersen, S., Jensen, S. L., Thestrup-Pedersen, K., and Larsen, C. G. Identification of functional domains on interleukin-10. Proc. Natl. Acad. Sci. USA 94: 14620-14625, 1997.

17. Knappe, A., Hor, S., Wittmann, S. and Fickenscher, H. Indution of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with Herpesvirus saimiri. J. Virology. 74: 3881-3887, 2000.

18. Kotenko, S.V. and Pestka, S. Jak-Stat signal-transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene. 19:2557-1565, 2000.

19. Kotenko, S.V. The family of IL-10-related cytokines and their receptors: related, but to what exernt? Cytokine & Growth Factor Reviews. 13: 223-240, 2000.

20. Kotenko, S.V., Izotova, L.S., Mirochnitchenko, O.V., Esterova, E., Dickensheets, H., Donnelly, R.P. and Pestka, S. Identification of the functional interleukin-22 (IL-22) receptor cmplex: the IL-10R2 chain (IL-10 beta) is a common chaion of both the IL-10 and Il-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol chem. 267: 2725-2732, 2001.

21. Kotenko, S.V., Izotova, L.S., Mirochnitchenko, O.V., Esterova, E., Dickensheets, H., Donnelly, R.P. and Pestka, S. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity.J. Immunol. 166: 7096-7103, 2001b.

22. Lecart, S., Morel, F., Noraz, N., Pene, P., Garcia, M., Boniface, K., Lecron, J.C. and Yssel, H. IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a functiona IL-22 receptor on activated human B cell. International Immunology. 14: 1351-1356, 2002.

23. Lejeune, D., Dumoutier, L., Constantinescu, S., Kruijer, W., Schuringa, J.J. and Renauld, J.C. IL-22 activates the JAK/STAT, ERK, JNK and p38 MAP kinase pathways in a rat hepatoma cell line: shared and distinct pathways from IL-10. J. Biol. Chem., 2002.

24. 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- α and results in cell apoptosis through TNF- α. J. Immuno. 169: 4288-4297, 2002.

25. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. and O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19: 683-765, 2001.

26. Nagem, R.A.P., Colau, D., Dumoutier, L., Renauld, J.C., Ogata, C. and Polikarpov, L. Crystal structure of recombinant human interleukin-22. Structure. 10: 1051-1062, 2002.

27. Norman, J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg. 175: 76-83, 1998.

28. O'Farrell, A.M., Liu, Y., Moore, K.W. and Mui, A.L. IL-10inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidience for Stat3-dependent and -independent pathways. EMBO J. 17: 1006-1018, 1998.

29. Rousset, F., Garcia, E., Defrance, T., Peronne, C., Vezzio, N., Hsu, D., Kastelein, R., Moore, K. and Banchereau, J. Interleukin-10 is a potent growth and differentiation factor foor activated human B lymphocytes. Proc. Natl. Acad. Sci. USA 89: 1890-1893, 1992.

30. Sarkar, D., Su. Z.Z., Lebedeva, I.V., Sauane, M., Gopalkrishnan, R.V., Dent, P. and Fisher, P.B. mda-7 (IL-24): Signaling and functional roles. Bio Techniques. 33: S30-S39, 2002.

31. Sarker, D., Su, Z.Z., Lebedeva, I.V., Sauane, M., Gpalkrishnan, R.V., Valerie, K., Dent, P. and Fisher, P. 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. USA. 99: 10054-10059, 2002.
32. Shimbara, A., christodoulpoulos, P., Soussi-Gounni, A., Olivenstein, R., Nakamura, Y., Levitt, R.C., Nicolaides, N.C., Holroyd, K.J., Tsicopoulos, A., Lafitte, J.J., Wallaert, B. and Hamid, Q.A. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J. Allergy Clin. Immunol. 104: 108-115, 1999.

33. Temann, U.A., Ray, P. and Flavell, R.A. Pulmonary overexpression of IL-9 induceds Th2 cytokine expression, leading to immune patholoogy. J. Clin. Invest. 109: 29-39, 2002.

34. Thompson-Snipes, L., Dhar, V., Bond, M., Mosmann, T., Moore, K. and Rennick, D. Interleukin-10: a novel stimulatory factor for mast cells and their progenitors. J. Exp. Med. 173: 507-510, 1991.

35. Wei, C.C., Ho, T.W., Liang, W.G., Chen, G.Y. and Chang, M.S. Cloning and characterization of mouse IL-22 binding protein. Genes and Immunity. 4: 204-211, 2003.

36. Wolk, K., Kunz, S., Asadullah, K. and Sabat, R. Cutting Edge: Immune cells as sources and targets of the IL-10 family member? J. Immuno. 168: 5397-5402, 2002.

37. 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: 31335-31339, 2000.

38. 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 receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Natl. Acad. Sci. USA 98: 9511-9516, 2001.