近來對於過敏性呼吸道發炎現象的了解是認為在發炎反應是以活化型T細胞居中指揮，此外，目前也已知道在呼吸道黏膜中的T細胞可藉由分泌IL-10調控第二型幫助性T細胞所衍生的呼吸道過敏現象以及發炎反應，因此，IL-10可能在過敏性氣喘病程中扮演一重要的負向調控角色；因而我們的目的便是想研究在包括IL-10、IL-19、IL-20、 MDA-7 (IL-24)，以及AK155 (IL-26)在內的IL-10家族中的一員，IL-19，是否也與氣喘的致病機轉有關。由實驗室之前的研究得知老鼠IL-19可促使IL-6以及TNF-α生成，同時亦可導致老鼠單核球細胞進行細胞凋亡(apoptosis)以及產生ROS反應。為了探討IL-19是否與氣喘的致病機轉有關，我們建立了ELISA系統進行氣喘病人血清中IL-19的含量分析並且發現氣喘病人血中IL-19的量高於正常個體兩倍以上，同時血中IL-19含量較高的病人，其IL-4以及IL-13的血中含量也有較高現象；我們更進一步建立了氣喘動物模式研究IL-19與氣喘之間的關聯性，發現在患有氣喘症狀的小鼠IL-19含量是未患有氣喘的正常對照組的兩倍，同時可在氣喘小鼠肺部觀察到IL-19轉錄本的表現，此外，利用肌肉電擊(intramuscular electroporation)方式將IL-19基因送入小鼠體內發現IL-19可以在正常小鼠體內促使IL-4以及IL-5生成，但IL-13在正常小鼠體內的表現卻無上升現象，然而，以相同方式將IL-19基因送入氣喘小鼠時卻可觀察到IL-13表現量上升的現象；在in vitro情況下IL-19可刺激活化型的T細胞產生IL-4、IL-5、IL-10以及IL-13，因此，T細胞的活化與否對於IL-13的生成是很重要的，因若在未經刺激活化的T細胞處理IL-19則無法促使IL-13生成，總結以上各點結果可知IL-19可能藉由調控活化型T細胞IL-13的產生而在氣喘致病機轉中扮演一重要角色。

　　The current paradigm for allergic airway inflammation regards the activated T lymphocyte as the choirmaster of the inflammatory response. It has been shown that T cells secreting IL-10 in the respiratory mucosa can regulate Th2-induced airway hyperreactivity and inflammation. It suggests that IL-10 plays an important inhibitory role in allergic asthma. Our aims, therefore, were to explore if IL-19, a member of IL-10 family which includes IL-10, IL-19, IL-20, MDA-7 (IL-24)， and AK155 (IL-26) was associated with pathogenesis of asthma. Our previous study showed mouse IL-19 induced the production of IL-6 and TNF-α. Mouse IL-19 also induced mouse monocytes apoptosis and production of reactive oxygen species (ROS). To explore IL-19 is associated with pathogenesis of asthma, we employed ELISA to analyze the serum level of IL-19 in the asthma patients and found that IL-19 level in the patients was two-fold over the normal control. Patients with high level of IL-19 also contained high level of IL-4 and IL-13.We further develops an asthma animal model to study the relationship between IL-19 and asthma. IL-19 level in asthma mice was also two-fold over the control mice and the transcript of IL-19 was also induced in the lung of asthma mice. Delivery of IL-19 gene into mice by intramuscular electroporation showed that IL-19 up-regulated IL-4, IL-5 and IL-10 in vivo. IL-13 was not up-regulated by IL-19 in normal mice. However, IL-19 up-regulated IL-13 in asthma mice. In vitro, IL-19 also induced IL-4, IL-5, IL-10 and IL-13 production by the activated T cells. Activation of T cells is required for induction of IL-13 because IL-19 did not induce IL-13 production on unstimulated T cells. Taken together, these results demonstrated that IL-19 may play an important role in pathogenesis of asthma by regulating IL-13 production on activated T cells.

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

2. Ding, Y., L. Qin, S.V. Kotenko, S. Pestka, and J.S. Bromberg. 2000. A single
amino acid determines the immunostimulatory activity of interleukin 10. J. Exp.
Med. 191:213-224.

3. Go, N.F., B.E. Castle, R. Barrett, R. Kastelein, W. Dang, T.R. Mosmann, K.W.
Moore, and M. Howard. 1990. Interleukin 10, a novel B cell stimulatory factor:
unresponsiveness of X chromosome-linked immunodeficiency B cells. J. Exp.
Med.172:1625-1631.

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

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

6. de Waal, M. R.. 1998. Interleukin-10. In Cytokine. A.R. Mire-Sluis, and R. Thorpe,
editors. Academic Press, San Diego, CA, 151 pp.

7. de Waal, M.R., J. Abrams, B. Bennett, C.G. Figdor, and J.E. de Vries. 1991.
Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174:1209-1220.

8. Liao, Y.C., W.G. Liang, F.W. Chen, J.H. Hsu, J.J. Yang, and M.S. Chang. 2002.
IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis
through TNF-alpha. J. Immunol. 169: 4288-4297.

9. Gallagher, G., H. Dickensheets, J. Eskdale, L.S. Izotova, O.V. Mirochnitchenko,
J.D. Peat, N. Vazquez, S. Pestka, R.P. Donnelly, and S.V. Kotenko. 2000.
Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel
homologue of human interleukin-10 (IL-10). Genes Immun. 1:442-450.

10. Swain, S.L., A.D. Weinberg, M. English, and G. Huston. 1990. IL-4 directs the
development of TH2-like helper effectors. J. Immunol. 145, 3796–3806.

11. Seder, R.A., W.E. Paul, M.M. Davis, and B. Fazekas de St Groth.1992. The presence of interleukin 4 during in vitro priming determines the lymphokine- producing potential CD4+ T cells from T cell receptor transgenic mice. J. Exp.Med. 176:1091-1098.

12. Kopf, M., M.G. Le Gros, M.C. Bachmann, Lamers, H. Bluethmann, and G. Kohler.1993. Disruption of the murine IL-4 gene blocks TH2 cytokine responses. Nature. 362:245–248.

13. Clutterbuck, E.J., E.M. Hirst, and C.J. Sanderson. 1989. Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures:
comparison and interaction with IL-1, IL-3, IL-6, and GM-CSF. Blood. 73:1504-12.

14. Kung, T.T., D.M. Stelts, and R.W. Chapman. 1995. Involvement of IL-5 in a murine model of allergic pulmonary inflammation: prophylactic and therapeutic effect of an anti-IL-5 antibody. Am. J. Respir. Cell. Mol. Biol. 13: 360–365.

15. Van Oosterhout, A.J., D. Fattah, and F.P. Nijkamp. 1995. Eosinophil infiltration precedes development of airway hyperreactivity and mucosal exudation after intranasal administration of interleukin-5 to mice. J. Allergy. Clin. Immunol. 96:104–112.
16. Grunig, G., M. Warnock, A.E. Wakil, R. Venkayya, F. Brombacher, D.M. Rennick, D. Sheppard, M. Mohrs, D.D. Donaldson, R.M. Locksley, and D.B. Corry. 1998. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 282:2261–2263.

17. Wills-Karp, M., J. Luyimbazi, X. Xu, B. Schofield, T.Y. Neben, C.L. Karp, and D.D. Donaldson. 1998. Interleukin-13: central mediator of allergic asthma. Science. 282:2258–2261.

18. Zuany-Amorim, C., E. Sawicka, C. Manlius, A. Le Moine, L.R. Brunet, D.M. Kemeny, G. Bowen, G. Rook, and C. Walker. 2002. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat. Med. 8:625-9.

19. Yu, C.K., C.M. Shieh, and H.Y. Lei. 1999. Repeated intratracheal inoculation of house dust mite Dermatophagoides farinae induces pulmonary eosinophilic inflammation and IgE antibody in mice. J. Allergy. Clin. Immunol. 104:228-236.

20. Finkelman, F.D., I.M. Katona, J.F. Jr Urban, J. Holmes, J. Ohara, A.S. Tung, J.V. Sample, and W.E. Paul. 1988. IL-4 is required to generate and sustain in vivo IgE responses. J. Immunol. 141:2335–2341.

21. McKenzie, G.J., C.L. Emson, S.E. Bell, S. Anderson, P. Fallon, G. Zurawski, R. Murray, R. Grencis, and A.N. McKenzie. 1998. Impaired development of TH2 cells in IL-13-deficient mice. Immunity. 9:423–432.

22. Emson, C.L., S.E. Bell, A. Jones, W. Wisden, and A.N. McKenzie.1998. Interleukin (IL)-4-independent induction of immunoglobulin (Ig)E, and perturbation of T cell development in transgenic mice expressing IL-13. J. Exp. Med. 188:399–404.

23. Parronchi, P., F. Brugnolo, F. Annunziato, C. Manuelli, S. Sampognaro, C. Mavilia, S. Romagnani, and E. Maggi. 1999. Phosphorothioate oligodeoxynucleotides promote the in vitro development of human allergen-specific CD4+ T cells into Th1 effectors. J. Immunol. 163:5946-53.

24. Randolph, D.A., C.J. Carruthers, S.J. Szabo, K.M. Murphy, and D.D. Chaplin. 1999. Modulation of airway inflammation by passive transfer of allergen-specific Th1 and Th2 cells in a mouse model of asthma. J. Immunol. 162:2375–83.

25. Hansen, G., G. Berry, R.H. DeKruyff, and D.T. Umetsu. 1999. Allergen-specific Th1 cells fail to counterbalance Th2 cell induced airway hyperreactivity but cause
severe airway inflammation. J. Clin. Invest. 103:175–83.

26. Dahl, M.E., K. Dabbagh, D. Liggitt, S. Kim, and D.B. Lewis. 2004. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat. Immunol. 5:337-43.

27. Akbari, O.,P. Stock,R. H DeKruyff, and D. T Umestsu. 2003. Role of redulatory T cells in allergy and asthma. Curr. Opin. Immunol. 15:627-633.

28. Horton, H.M., D. Anderson, P. Hernandez, K.M. Barnhart, J.A. Norman, and S.E. Parker. 1999. A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon alpha. Proc. Natl. Acad. Sci. U. S. A. 96:1553-1558.

29. Hsu, D.H., R. de Waal Malefyt, D.F. Fioretino, M.N. Dang, P. Vieira, J. de Vries, H. Spits, T.R. Mosmann, K.W. Moore. 1990.Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science. 250:830-832.

30. Jinquan, T., C.G. Larsen, B. Gessser, K. Matsushima, and K. Thestrup-Pedersen. 1993. Human IL-10 is a chemoattractant for CD8+ T lymphocytes and an inhibitor of IL-8-induced CD4+ T lymphocyte migration. J. Immunol. 151:4545-4551.

31. Knappe, A., S. Hor, S. Wittmann, and H. Fickenscher, 2000. Induction of a novel cellular homolog of interleukin-10, Ak155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74:3881-3887.

32. Kotenko, S.V., L.S. Izotova, O.V. Mirochnitchenko, E. Esterova, H. Dickensheets, R.P. Donnelly, and S. Pestka. 2000. Identificationof the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10R) is a common chain of both the IL-10 and IL-22 (IL-TIF) receptor complexes. J. Biol. Chem. 276:2725-2732.

33. Kube, D., C. Platzer, A. Von Knethen, H. Straub, H. Bohlen, M. Hafner, and H. Tesch. 1995. Isolation of the human interleukin 10 promoter: Characterization of the promoter activity in Burkitt's lymphoma cell lines. Cytokine. 7: 1-7.

34. Laure, D., L. Caroline, L. Diane, V.K. Sergei, and R. Christophe. 2001. Cutting Edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J. Immunol. 167:3545-3549.

35.Lehmann, M.H. 1998. Recombinant human granulocyte-macrophage colony-stimulating factor triggers interleukin-10 expression in the monocytic cell line U937. Mol. Immunol. 35:479-485.

36. Li, S., F.C. MacLaughlin, J.G. Fewell, Y. Li, V. Mehta, M.F. French, J.L. Nordstrom, M. Coleman, N.S. Belagali, R.J. Schwartz, and L.C. Smith. 1999. Increased level and duration of expression in muscle by co-expression of a transactivator using plasmid systems. Gene. Ther. 6:2005-2011.

37. Li, S., X. Zhang, X. Xia, L. Zhou, R. Breau, J. Suen, and E. Hanna. 2001. Intramuscular electroporation delivery of IFN-alpha gene therapy for inhibition of tumor growth located at a distant site. Gene. Ther. 8:400-407.
38. Liao, Y.C., W.G. Liang, F.W. Chen, J.H. Hsu, J.J. Yang, M.S.Chang. 2002. IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha. J. Immunol. 169:4288-4297.

39. MacNeil, I.A., T. Suda, K.W. Moore, T.R. Mosmann, A. Zlotnik. 1990. IL-10, a novel growth cofactor for mature and immature T cells. J. Immunol. 145: 4167-4173.

40. Maruyama, H., K. Ataka, F. Gejyo, N. Higuchi, Y. Ito, H. Hirahara, I. Imazeki, M. Hirata, F. Ichikawa, T. Neichi, H. Kikuchi, M. Sugawa, and J. Miyazaki. 2001. Long-term production of erythropoietin after electroporation-mediated transfer of plasmid DNA into the muscles of normal and uremic rats. Gene. Ther. 8:461-468.

41. Mathiesen, I. 1999. Electropermeabilization of skeletal muscle enhances gene transfer in vivo. Gene, Ther, 6:508-514.
42. Mignon-Godefroy, K., O. Rott, M.P. Brazillet, and J. Charreire. 1995. Curative and protective effects of IL-10 in experimental autoimmune thyroiditis (EAT). J. Immunol. 154:6634-6643.

43. Mir, L.M., M.F. Bureau, J. Gehl, R. Rangara, D. Rouy, J.M. Caillaud, P. Delaere, D. Branellec, B. Schwartz, and D. Scherman. 1999.High-efficiency gene transfer into skeletal muscle mediated by electric pulses. Proc. Natl. Acad. Sci. U. S. A. 96:4262.
44. Moore, K.W., A. O’Garra, R. de waal Malefyt, P.Vieira, T.R. Mosmann. 1993. Interleukin-10. Annu. Rev. Immunol. 11:165-190.
45. Mosmann, T.R. 1991.Regulation of immune responses by T cells with different cytokine secretion phenotypes: role of a new cytokine, cytokine synthesis inhibitory factor (IL10). Int. Arch. Allergy. Appl. Immunol. 94:110-115.

46. Mumper, R.J., J. Wang, S.L. Klakamp, H. Nitta, K. Anwer, F. Tagliaferri, and A.P. Rolland. 1998. Protective interactive noncondensing (PINC) polymers for enhanced plasmid distribution and expression in rat skeletal muscle. J. Control. Release. 52:191-203.

47. Munoz, C., J. Carlet, C. Fitting, B. Misset, J.P. Bleriot, J.M. Cavaillon. 1991. Dysregulation of in vitro cytokine production by monocytes during sepsis. J. Clin. Invest. 88:1747-1754.

48. Nishi, T., K. Yoshizato, S. Yamashiro, H. Takeshima, K. Sato, K. Hamada, I. Kitamura, T. Yoshimura, H. Saya, J. Kuratsu, and Y. Ushio. 1996. High-efficiency in vivo gene transfer using intraarterial plasmid DNA injection following in vivo electroporation. Cancer. Res. 56:1050-1055.

49. O'Malley, B.W.Jr., K.A.Cope, , C.S.Johnson, and M.R. Schwartz. 1997. A new immunocompetent murine model for oral cancer. Arch. Otolaryngol. Head. Neck. Surg. 123:20-24.