IL-35通过增强髓源性细胞聚积和肿瘤血管生成促进肿瘤生长
摘要
白介素35（IL-35）是白介素12（IL-12）家族的新成员，由p35亚基和EBI3亚基组成，受体是IL-12Rβ2和gp130。现已证明IL-35可以通过其受体发挥抗炎作用，其在多种自身免疫性疾病中的作用已有比较深入的研究，但在肿瘤方面目前为止还未见有文献报道。
虽然有研究表明IL-35由调节T细胞（Treg）产生，但基因表达分析显示IL-35有着更广泛的表达分布，包括在多种肿瘤组织内的表达。首先，我们利用人体肿瘤组织进行免疫组化染色，发现在人巨型B细胞淋巴瘤、鼻咽癌、皮肤黑色素瘤和淋巴结转移性黑色素瘤中均发现有IL-35的表达。我们通过转染法将IL-35导入浆细胞瘤J558和黑色素瘤B16细胞中，并经过药物筛选得到稳转细胞株，以此研究肿瘤源性的IL-35在肿瘤免疫和肿瘤发生方面的作用。
结果我们发现IL-35对肿瘤细胞在体外的生长不产生影响，但在野生型和免疫缺陷型小鼠体内对肿瘤生长有明显的促进作用。肿瘤源性的IL-35增加了CD11b+Gr1+髓源性细胞在肿瘤微环境内的聚集，并且促进肿瘤血管的生长。在正常小鼠体内，肿瘤特异性的CTL免疫应答被减弱了。IL-35不能直接抑制特异性CD8+T细胞的活性、分化以及功能。然而，经IL-35处理的肿瘤细胞上调了gp130的表达，同时降低了自身对CTL杀伤作用的敏感性。
IL-35is a member of the IL-12family of cytokines consisting of IL-12p35subunitand IL-12p40-related protein subunit, EBV-induced gene3(EBI3). IL-35functionsthrough IL-35R (IL-12Rβ2and gp130) and has a potent immune suppressive activity.Studies demonstrated that IL-35involves in many autoimmune diseases, but few research ison IL-35in tumor.
Although IL-35has been demonstrated to be produced by regulatory T cells, geneexpression analysis has revealed that IL-35is likely to have wider distribution includingexpression in cancer cells. In this study we have demonstrated that IL-35is produced inhuman cancer tissues such as large B cell lymphoma, nasopharyngeal carcinoma andmelanoma. In order to determine the roles of tumor-derived IL-35in tumorigenesis andtumor immunity, we generated IL-35producing plasmacytoma J558and B16melanomacells, and observed that the expression of IL-35in cancer cells does not affect their growthand survival in vitro, but stimulates tumorigenesis in both immune competent and Rag1/2deficient mice. Tumor-derived IL-35increases CD11b+Gr1+myeloid cell accumulation intumor microenvironment, and thereby promotes tumor angiogenesis. In immune competentmice, spontaneous CTL responses to tumors are diminished. IL-35does not directly inhibittumor antigen specific CD8+T cell activation, differentiation and effector functions.However, IL-35-treated cancer cells had increased expression of gp130and reducedsensitivity to CTL destruction. Thus, our study indicates novel functions of IL-35inpromoting tumor growth via enhancing myeloid cell accumulation, tumor angiogenesis andsuppression of tumor immunity.
虽然有研究表明IL-35由调节T细胞（Treg）产生，但基因表达分析显示IL-35有着更广泛的表达分布，包括在多种肿瘤组织内的表达。首先，我们利用人体肿瘤组织进行免疫组化染色，发现在人巨型B细胞淋巴瘤、鼻咽癌、皮肤黑色素瘤和淋巴结转移性黑色素瘤中均发现有IL-35的表达。我们通过转染法将IL-35导入浆细胞瘤J558和黑色素瘤B16细胞中，并经过药物筛选得到稳转细胞株，以此研究肿瘤源性的IL-35在肿瘤免疫和肿瘤发生方面的作用。
结果我们发现IL-35对肿瘤细胞在体外的生长不产生影响，但在野生型和免疫缺陷型小鼠体内对肿瘤生长有明显的促进作用。肿瘤源性的IL-35增加了CD11b+Gr1+髓源性细胞在肿瘤微环境内的聚集，并且促进肿瘤血管的生长。在正常小鼠体内，肿瘤特异性的CTL免疫应答被减弱了。IL-35不能直接抑制特异性CD8+T细胞的活性、分化以及功能。然而，经IL-35处理的肿瘤细胞上调了gp130的表达，同时降低了自身对CTL杀伤作用的敏感性。
IL-35is a member of the IL-12family of cytokines consisting of IL-12p35subunitand IL-12p40-related protein subunit, EBV-induced gene3(EBI3). IL-35functionsthrough IL-35R (IL-12Rβ2and gp130) and has a potent immune suppressive activity.Studies demonstrated that IL-35involves in many autoimmune diseases, but few research ison IL-35in tumor.
Although IL-35has been demonstrated to be produced by regulatory T cells, geneexpression analysis has revealed that IL-35is likely to have wider distribution includingexpression in cancer cells. In this study we have demonstrated that IL-35is produced inhuman cancer tissues such as large B cell lymphoma, nasopharyngeal carcinoma andmelanoma. In order to determine the roles of tumor-derived IL-35in tumorigenesis andtumor immunity, we generated IL-35producing plasmacytoma J558and B16melanomacells, and observed that the expression of IL-35in cancer cells does not affect their growthand survival in vitro, but stimulates tumorigenesis in both immune competent and Rag1/2deficient mice. Tumor-derived IL-35increases CD11b+Gr1+myeloid cell accumulation intumor microenvironment, and thereby promotes tumor angiogenesis. In immune competentmice, spontaneous CTL responses to tumors are diminished. IL-35does not directly inhibittumor antigen specific CD8+T cell activation, differentiation and effector functions.However, IL-35-treated cancer cells had increased expression of gp130and reducedsensitivity to CTL destruction. Thus, our study indicates novel functions of IL-35inpromoting tumor growth via enhancing myeloid cell accumulation, tumor angiogenesis andsuppression of tumor immunity.
引文
1. Devergne, O., M. Birkenbach, and E. Kieff.1997. Epstein-Barr virus-induced gene3and the p35subunit of interleukin12form a novel heterodimeric hematopoietin. Proc Natl Acad Sci U S A94:12041-12046.
2. Niedbala, W., X. Q. Wei, B. Cai, A. J. Hueber, B. P. Leung, I. B. McInnes, and F. Y. Liew.2007.IL-35is a novel cytokine with therapeutic effects against collagen-induced arthritis through theexpansion of regulatory T cells and suppression of Th17cells. Eur J Immunol37:3021-3029.
3. Collison, L. W., C. J. Workman, T. T. Kuo, K. Boyd, Y. Wang, K. M. Vignali, R. Cross, D. Sehy, R. S.Blumberg, and D. A. Vignali.2007. The inhibitory cytokine IL-35contributes to regulatory T-cellfunction. Nature450:566-569.
4. Collison, L. W., G. M. Delgoffe, C. S. Guy, K. M. Vignali, V. Chaturvedi, D. Fairweather, A. R.Satoskar, K. C. Garcia, C. A. Hunter, C. G. Drake, P. J. Murray, and D. A. Vignali.2012. Thecomposition and signaling of the IL-35receptor are unconventional. Nat Immunol13:290-299.
5. Li, X., J. Mai, A. Virtue, Y. Yin, R. Gong, X. Sha, S. Gutchigian, A. Frisch, I. Hodge, X. Jiang, H.Wang, and X. F. Yang.2012. IL-35is a novel responsive anti-inflammatory cytokine--a new systemof categorizing anti-inflammatory cytokines. PLoS One7: e33628.
6. Chaturvedi, V., L. W. Collison, C. S. Guy, C. J. Workman, and D. A. Vignali.2011. Cutting edge:Human regulatory T cells require IL-35to mediate suppression and infectious tolerance. J Immunol186:6661-6666.
7. Bardel, E., F. Larousserie, P. Charlot-Rabiega, A. Coulomb-L'Hermine, and O. Devergne.2008.Human CD4+CD25+Foxp3+regulatory T cells do not constitutively express IL-35. J Immunol181:6898-6905.
8. Huang, C. H., E. X. Loo, I. C. Kuo, G. H. Soh, D. L. Goh, B. W. Lee, and K. Y. Chua.2011. Airwayinflammation and IgE production induced by dust mite allergen-specific memory/effector Th2cellline can be effectively attenuated by IL-35. J Immunol187:462-471.
9. Li, X., J. Mai, A. Virtue, Y. Yin, R. Gong, X. Sha, S. Gutchigian, A. Frisch, I. Hodge, X. Jiang, H.Wang, and X. F. Yang.2012. IL-35is a novel responsive anti-inflammatory cytokine--a new systemof categorizing anti-inflammatory cytokines. PLoS One7: e33628.
10.Devergne, O., A. Coulomb-L'Hermine, F. Capel, M. Moussa, and F. Capron.2001. Expression ofEpstein-Barr virus-induced gene3, an interleukin-12p40-related molecule, throughout humanpregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. Am J Pathol159:1763-1776.
11. Niedobitek, G., D. Pazolt, M. Teichmann, and O. Devergne.2002. Frequent expression of theEpstein-Barr virus (EBV)-induced gene, EBI3, an IL-12p40-related cytokine, in Hodgkin andReed-Sternberg cells. J Pathol198:310-316.
12.Poleganov, M. A., M. Bachmann, J. Pfeilschifter, and H. Muhl.2008. Genome-wide analysis displaysmarked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1cells: critical role of twokappaB binding sites in the human EBI3promotor. Mol Immunol45:2869-2880.
13.Nishino, R., A. Takano, H. Oshita, N. Ishikawa, H. Akiyama, H. Ito, H. Nakayama, Y. Miyagi, E.Tsuchiya, N. Kohno, Y. Nakamura, and Y. Daigo.2011. Identification of Epstein-Barr virus-inducedgene3as a novel serum and tissue biomarker and a therapeutic target for lung cancer. Clin CancerRes17:6272-6286.
14.Larousserie, F., E. Bardel, S. Pflanz, B. Arnulf, C. Lome-Maldonado, O. Hermine, L. Bregeaud, M.Perennec, N. Brousse, R. Kastelein, and O. Devergne.2005. Analysis of interleukin-27(EBI3/p28)expression in Epstein-Barr virus-and human T-cell leukemia virus type1-associated lymphomas:heterogeneous expression of EBI3subunit by tumoral cells. Am J Pathol166:1217-1228.
15.Liyanage, U. K., T. T. Moore, H. G. Joo, Y. Tanaka, V. Herrmann, G. Doherty, J. A. Drebin, S. M.Strasberg, T. J. Eberlein, P. S. Goedegebuure, and D. C. Linehan.2002. Prevalence of regulatory Tcells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breastadenocarcinoma. J Immunol169:2756-2761.
16.Wolf, D., A. M. Wolf, H. Rumpold, H. Fiegl, A. G. Zeimet, E. Muller-Holzner, M. Deibl, G. Gastl, E.Gunsilius, and C. Marth.2005. The expression of the regulatory T cell-specific forkhead boxtranscription factor FoxP3is associated with poor prognosis in ovarian cancer. Clin Cancer Res11:8326-8331.
17.Talebian, F., J. Q. Liu, Z. Liu, M. Khattabi, Y. He, R. Ganju, and X. F. Bai.2012. Melanoma cellexpression of CD200inhibits tumor formation and lung metastasis via inhibition of myeloid cellfunctions. PLoS One7: e31442.
18.Nagaraj, S., and D. I. Gabrilovich.2008. Tumor escape mechanism governed by myeloid-derivedsuppressor cells. Cancer Res68:2561-2563.
19.Gabrilovich, D. I., and S. Nagaraj.2009. Myeloid-derived suppressor cells as regulators of theimmune system. Nat Rev Immunol9:162-174.
1. Collison, L.W., et al., The inhibitory cytokine IL-35contributes to regulatory T-cell function.Nature,2007.450(7169): p.566-9.
2. Collison, L.W. and D.A. Vignali, Interleukin-35: odd one out or part of the family? Immunol Rev,2008.226: p.248-62.
3. Collison, L.W., et al., The composition and signaling of the IL-35receptor are unconventional.Nature Immunology,2012.13(3): p.290-9.
4. Bardel, E., et al., Human CD4+CD25+Foxp3+regulatory T cells do not constitutively expressIL-35. J Immunol,2008.181(10): p.6898-905.
5. Chaturvedi, V., et al., Cutting edge: Human regulatory T cells require IL-35to mediate suppressionand infectious tolerance. J Immunol,2011.186(12): p.6661-6.
6. Li, X., et al., IL-35is a novel responsive anti-inflammatory cytokine--a new system of categorizinganti-inflammatory cytokines. PLoS One,2012.7(3): p. e33628.
7. Devergne, O., et al., A novel interleukin-12p40-related protein induced by latent Epstein-Barrvirus infection in B lymphocytes. J Virol,1996.70(2): p.1143-53.
8. Whitehead, G.S., et al., IL-35production by inducible costimulator (ICOS)-positive regulatory Tcells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol,2012.129(1): p.207-15e1-5.
9. Herrick, C.A. and K. Bottomly, To respond or not to respond: T cells in allergic asthma. Nat RevImmunol,2003.3(5): p.405-12.
10. Larche, M., D.S. Robinson, and A.B. Kay, The role of T lymphocytes in the pathogenesis of asthma.J Allergy Clin Immunol,2003.111(3): p.450-63; quiz464.
11. Kips, J.C., et al., Effect of SCH55700, a humanized anti-human interleukin-5antibody, in severepersistent asthma: a pilot study. Am J Respir Crit Care Med,2003.167(12): p.1655-9.
12. Leckie, M.J., et al., Effects of an interleukin-5blocking monoclonal antibody on eosinophils,airway hyper-responsiveness, and the late asthmatic response. Lancet,2000.356(9248): p.2144-8.
13. O'Byrne, P.M., The demise of anti IL-5for asthma, or not. Am J Respir Crit Care Med,2007.176(11): p.1059-60.
14. McKinley, L., et al., TH17cells mediate steroid-resistant airway inflammation and airwayhyperresponsiveness in mice. J Immunol,2008.181(6): p.4089-97.
15. Song, C., et al., IL-17-producing alveolar macrophages mediate allergic lung inflammation relatedto asthma. J Immunol,2008.181(9): p.6117-24.
16. Atkinson, M.A. and G.S. Eisenbarth, Type1diabetes: new perspectives on disease pathogenesisand treatment. Lancet,2001.358(9277): p.221-9.
17. Bettini, M., et al., Prevention of Autoimmune Diabetes by Ectopic Pancreatic beta-Cell Expressionof Interleukin-35. Diabetes,2012.61(6): p.1519-26.
18. Xavier, R.J. and D.K. Podolsky, Unravelling the pathogenesis of inflammatory bowel disease.Nature,2007.448(7152): p.427-34.
19. Wirtz, S., et al., Interleukin-35mediates mucosal immune responses that protect againstT-cell-dependent colitis. Gastroenterology,2011.141(5): p.1875-86.
20. Courtenay, J.S., et al., Immunisation against heterologous type II collagen induces arthritis in mice.Nature,1980.283(5748): p.666-8.
21. Lubberts, E., et al., IL-17promotes bone erosion in murine collagen-induced arthritis through lossof the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol,2003.170(5):p.2655-62.
22. Rohn, T.A., et al., Vaccination against IL-17suppresses autoimmune arthritis andencephalomyelitis. Eur J Immunol,2006.36(11): p.2857-67.
23. Niedbala, W., et al., IL-35is a novel cytokine with therapeutic effects against collagen-inducedarthritis through the expansion of regulatory T cells and suppression of Th17cells. Eur J Immunol,2007.37(11): p.3021-9.
24. Kochetkova, I., et al., IL-35stimulation of CD39+regulatory T cells confers protection againstcollagen II-induced arthritis via the production of IL-10. J Immunol,2010.184(12): p.7144-53.
2. Niedbala, W., X. Q. Wei, B. Cai, A. J. Hueber, B. P. Leung, I. B. McInnes, and F. Y. Liew.2007.IL-35is a novel cytokine with therapeutic effects against collagen-induced arthritis through theexpansion of regulatory T cells and suppression of Th17cells. Eur J Immunol37:3021-3029.
3. Collison, L. W., C. J. Workman, T. T. Kuo, K. Boyd, Y. Wang, K. M. Vignali, R. Cross, D. Sehy, R. S.Blumberg, and D. A. Vignali.2007. The inhibitory cytokine IL-35contributes to regulatory T-cellfunction. Nature450:566-569.
4. Collison, L. W., G. M. Delgoffe, C. S. Guy, K. M. Vignali, V. Chaturvedi, D. Fairweather, A. R.Satoskar, K. C. Garcia, C. A. Hunter, C. G. Drake, P. J. Murray, and D. A. Vignali.2012. Thecomposition and signaling of the IL-35receptor are unconventional. Nat Immunol13:290-299.
5. Li, X., J. Mai, A. Virtue, Y. Yin, R. Gong, X. Sha, S. Gutchigian, A. Frisch, I. Hodge, X. Jiang, H.Wang, and X. F. Yang.2012. IL-35is a novel responsive anti-inflammatory cytokine--a new systemof categorizing anti-inflammatory cytokines. PLoS One7: e33628.
6. Chaturvedi, V., L. W. Collison, C. S. Guy, C. J. Workman, and D. A. Vignali.2011. Cutting edge:Human regulatory T cells require IL-35to mediate suppression and infectious tolerance. J Immunol186:6661-6666.
7. Bardel, E., F. Larousserie, P. Charlot-Rabiega, A. Coulomb-L'Hermine, and O. Devergne.2008.Human CD4+CD25+Foxp3+regulatory T cells do not constitutively express IL-35. J Immunol181:6898-6905.
8. Huang, C. H., E. X. Loo, I. C. Kuo, G. H. Soh, D. L. Goh, B. W. Lee, and K. Y. Chua.2011. Airwayinflammation and IgE production induced by dust mite allergen-specific memory/effector Th2cellline can be effectively attenuated by IL-35. J Immunol187:462-471.
9. Li, X., J. Mai, A. Virtue, Y. Yin, R. Gong, X. Sha, S. Gutchigian, A. Frisch, I. Hodge, X. Jiang, H.Wang, and X. F. Yang.2012. IL-35is a novel responsive anti-inflammatory cytokine--a new systemof categorizing anti-inflammatory cytokines. PLoS One7: e33628.
10.Devergne, O., A. Coulomb-L'Hermine, F. Capel, M. Moussa, and F. Capron.2001. Expression ofEpstein-Barr virus-induced gene3, an interleukin-12p40-related molecule, throughout humanpregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. Am J Pathol159:1763-1776.
11. Niedobitek, G., D. Pazolt, M. Teichmann, and O. Devergne.2002. Frequent expression of theEpstein-Barr virus (EBV)-induced gene, EBI3, an IL-12p40-related cytokine, in Hodgkin andReed-Sternberg cells. J Pathol198:310-316.
12.Poleganov, M. A., M. Bachmann, J. Pfeilschifter, and H. Muhl.2008. Genome-wide analysis displaysmarked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1cells: critical role of twokappaB binding sites in the human EBI3promotor. Mol Immunol45:2869-2880.
13.Nishino, R., A. Takano, H. Oshita, N. Ishikawa, H. Akiyama, H. Ito, H. Nakayama, Y. Miyagi, E.Tsuchiya, N. Kohno, Y. Nakamura, and Y. Daigo.2011. Identification of Epstein-Barr virus-inducedgene3as a novel serum and tissue biomarker and a therapeutic target for lung cancer. Clin CancerRes17:6272-6286.
14.Larousserie, F., E. Bardel, S. Pflanz, B. Arnulf, C. Lome-Maldonado, O. Hermine, L. Bregeaud, M.Perennec, N. Brousse, R. Kastelein, and O. Devergne.2005. Analysis of interleukin-27(EBI3/p28)expression in Epstein-Barr virus-and human T-cell leukemia virus type1-associated lymphomas:heterogeneous expression of EBI3subunit by tumoral cells. Am J Pathol166:1217-1228.
15.Liyanage, U. K., T. T. Moore, H. G. Joo, Y. Tanaka, V. Herrmann, G. Doherty, J. A. Drebin, S. M.Strasberg, T. J. Eberlein, P. S. Goedegebuure, and D. C. Linehan.2002. Prevalence of regulatory Tcells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breastadenocarcinoma. J Immunol169:2756-2761.
16.Wolf, D., A. M. Wolf, H. Rumpold, H. Fiegl, A. G. Zeimet, E. Muller-Holzner, M. Deibl, G. Gastl, E.Gunsilius, and C. Marth.2005. The expression of the regulatory T cell-specific forkhead boxtranscription factor FoxP3is associated with poor prognosis in ovarian cancer. Clin Cancer Res11:8326-8331.
17.Talebian, F., J. Q. Liu, Z. Liu, M. Khattabi, Y. He, R. Ganju, and X. F. Bai.2012. Melanoma cellexpression of CD200inhibits tumor formation and lung metastasis via inhibition of myeloid cellfunctions. PLoS One7: e31442.
18.Nagaraj, S., and D. I. Gabrilovich.2008. Tumor escape mechanism governed by myeloid-derivedsuppressor cells. Cancer Res68:2561-2563.
19.Gabrilovich, D. I., and S. Nagaraj.2009. Myeloid-derived suppressor cells as regulators of theimmune system. Nat Rev Immunol9:162-174.
1. Collison, L.W., et al., The inhibitory cytokine IL-35contributes to regulatory T-cell function.Nature,2007.450(7169): p.566-9.
2. Collison, L.W. and D.A. Vignali, Interleukin-35: odd one out or part of the family? Immunol Rev,2008.226: p.248-62.
3. Collison, L.W., et al., The composition and signaling of the IL-35receptor are unconventional.Nature Immunology,2012.13(3): p.290-9.
4. Bardel, E., et al., Human CD4+CD25+Foxp3+regulatory T cells do not constitutively expressIL-35. J Immunol,2008.181(10): p.6898-905.
5. Chaturvedi, V., et al., Cutting edge: Human regulatory T cells require IL-35to mediate suppressionand infectious tolerance. J Immunol,2011.186(12): p.6661-6.
6. Li, X., et al., IL-35is a novel responsive anti-inflammatory cytokine--a new system of categorizinganti-inflammatory cytokines. PLoS One,2012.7(3): p. e33628.
7. Devergne, O., et al., A novel interleukin-12p40-related protein induced by latent Epstein-Barrvirus infection in B lymphocytes. J Virol,1996.70(2): p.1143-53.
8. Whitehead, G.S., et al., IL-35production by inducible costimulator (ICOS)-positive regulatory Tcells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol,2012.129(1): p.207-15e1-5.
9. Herrick, C.A. and K. Bottomly, To respond or not to respond: T cells in allergic asthma. Nat RevImmunol,2003.3(5): p.405-12.
10. Larche, M., D.S. Robinson, and A.B. Kay, The role of T lymphocytes in the pathogenesis of asthma.J Allergy Clin Immunol,2003.111(3): p.450-63; quiz464.
11. Kips, J.C., et al., Effect of SCH55700, a humanized anti-human interleukin-5antibody, in severepersistent asthma: a pilot study. Am J Respir Crit Care Med,2003.167(12): p.1655-9.
12. Leckie, M.J., et al., Effects of an interleukin-5blocking monoclonal antibody on eosinophils,airway hyper-responsiveness, and the late asthmatic response. Lancet,2000.356(9248): p.2144-8.
13. O'Byrne, P.M., The demise of anti IL-5for asthma, or not. Am J Respir Crit Care Med,2007.176(11): p.1059-60.
14. McKinley, L., et al., TH17cells mediate steroid-resistant airway inflammation and airwayhyperresponsiveness in mice. J Immunol,2008.181(6): p.4089-97.
15. Song, C., et al., IL-17-producing alveolar macrophages mediate allergic lung inflammation relatedto asthma. J Immunol,2008.181(9): p.6117-24.
16. Atkinson, M.A. and G.S. Eisenbarth, Type1diabetes: new perspectives on disease pathogenesisand treatment. Lancet,2001.358(9277): p.221-9.
17. Bettini, M., et al., Prevention of Autoimmune Diabetes by Ectopic Pancreatic beta-Cell Expressionof Interleukin-35. Diabetes,2012.61(6): p.1519-26.
18. Xavier, R.J. and D.K. Podolsky, Unravelling the pathogenesis of inflammatory bowel disease.Nature,2007.448(7152): p.427-34.
19. Wirtz, S., et al., Interleukin-35mediates mucosal immune responses that protect againstT-cell-dependent colitis. Gastroenterology,2011.141(5): p.1875-86.
20. Courtenay, J.S., et al., Immunisation against heterologous type II collagen induces arthritis in mice.Nature,1980.283(5748): p.666-8.
21. Lubberts, E., et al., IL-17promotes bone erosion in murine collagen-induced arthritis through lossof the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol,2003.170(5):p.2655-62.
22. Rohn, T.A., et al., Vaccination against IL-17suppresses autoimmune arthritis andencephalomyelitis. Eur J Immunol,2006.36(11): p.2857-67.
23. Niedbala, W., et al., IL-35is a novel cytokine with therapeutic effects against collagen-inducedarthritis through the expansion of regulatory T cells and suppression of Th17cells. Eur J Immunol,2007.37(11): p.3021-9.
24. Kochetkova, I., et al., IL-35stimulation of CD39+regulatory T cells confers protection againstcollagen II-induced arthritis via the production of IL-10. J Immunol,2010.184(12): p.7144-53.