DOI QR코드

DOI QR Code

TGF-β1 Expression by Proliferated Keratinocytes in the Skin of E-Irradiated Mice

E-ray를 조사한 쥐의 피부에서 증식된 keratinocyte에 의한 TGF-β1 발현

  • Yoon, A-Ran (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Kim, Do-Nyun (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Seo, Min-Koo (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Oh, Sang-Taek (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Seo, Jung-Seon (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Jun, Se-Mo (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea) ;
  • Cha, Jung-Ho (Department of Anatomy, College of Medicine, The Catholic University of Korea) ;
  • Lee, Seung-Deok (Department of Oriental Medicine, The Graduate School of Dongguk University) ;
  • Lee, Suk-Kyeong (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea)
  • 윤아란 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소) ;
  • 김도년 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소) ;
  • 서민구 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소) ;
  • 오상택 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소) ;
  • 서정선 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소) ;
  • 전세모 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소) ;
  • 차정호 (가톨릭대학교 의과대학 해부학교실) ;
  • 이승덕 (동국대학교 한의예과) ;
  • 이숙경 (가톨릭대학교 의과대학 의생명과학교실 면역생물학연구소)
  • Received : 2011.11.16
  • Accepted : 2011.11.27
  • Published : 2012.02.28

Abstract

In this study, we established a radiodermatitis animal model and investigated the change in immune cell proportions in the secondary lymphoid organs. The cells responsible for the increased transforming growth factor-${\beta}1$ (TGF-${\beta}1$) and interleukin-10 (IL-10) production in the lesions following irradiation were also investigated. The radiodermatitis model was constructed by locally exposing the posterior dorsal region of hairless-1 (HR-1) mice to 10 Gy electron (E)-ray/day for six consecutive days. The change in immune cell proportions was analyzed by FACS. Immunohistochemistry was carried out to detect the expression of cytokines and cell-specific markers in the skin. The proportions of antigen-presenting cells, T cells, and B cells in the lymph nodes and spleen were affected by E-irradiation. After irradiation, TGF-${\beta}1$ and IL-17 were co-localized in the papillary region of the dermis with keratin-14 (K-14)-positive cells rather than with regulatory T cells (Treg). IL-10 was not co-stained with Treg, T helper 17 (Th17) cells, dendritic cells, or macrophages. Our data indicate that TGF-${\beta}1$ is over-expressed mainly by proliferated keratinocytes in the lesions of a radiodermatitis animal model.

우리는 방사선피부염 동물 모델을 확립하여, 이차 면역 기관에서의 면역 세포 비율 변화를 관찰하였다. 또한, 방사선 조사에 의한 병소에서 transforming growth factor-${\beta}1$ (TGF-${\beta}1$)과 interlukin-10 (IL-10)의 발현을 증가시킨 세포를 분석하였다. Hairless-1 (HR-1) 쥐의 posterior dorsal 부위에 6 일간 매일 10 Gy 씩 electron (E)-ray를 국부 조사하여 방사선피부염 모델을 만들었다. FACS를 이용하여 면역 세포 비율의 변화를 분석한 결과 비장과 림프절에 존재하는 항원제시세포와 T 세포 및 B 세포들의 비율이 E-irradiation에 의해 영향을 받았다. 피부에서 세포 특이적인 마커와 사이토카인들의 발현 양상은 면역형광염색법으로 확인하였다. 방사선 조사 후, TGF-${\beta}1$과 interlukin-17 (IL-17)은 regulatory T 세포(Treg)보다 keratin-14 (K-14)를 발현하는 진피의 끝부분에서 높게 발현되었다. Interlukin-10 (IL-10)는 Treg 뿐만 아니라 T helper 17 (Th17) 세포, dendritic 세포, macrophage 중 어느 것과도 같은 위치에서 검출되지 않았다. 우리의 데이터는 방사선피부염 동물 모델의 병소 안에서, TGF-${\beta}1$이 증식된 keratinocyte에 과발현된다는 것을 나타낸다.

Keywords

References

  1. Banchereau, J. and R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392, 245-252. https://doi.org/10.1038/32588
  2. Bettelli, E., T. Korn, M. Oukka, and V. K. Kuchroo. 2008. Induction and effector functions of T(H)17 cells. Nature 453, 1051-1057. https://doi.org/10.1038/nature07036
  3. Billiard, F., V. Buard, M. Benderitter, and C. Linard. 2011. Abdominal gamma-radiation induces an accumulation of function-impaired regulatory T cells in the small intestine. Int. J. Radiat. Oncol. Biol. Phys. 80, 869-876. https://doi.org/10.1016/j.ijrobp.2010.12.041
  4. Blanpain, C., W. E. Lowry, A. Geoghegan, L. Polak, and E. Fuchs. 2004. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635-648. https://doi.org/10.1016/j.cell.2004.08.012
  5. Buschke, S., H. J. Stark, A. Cerezo, S. Pratzel-Wunder, K. Boehnke, J. Kollar, L. Langbein, C. H. Heldin, and P. Boukamp. 2011. A decisive function of transforming growth factor-beta/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes. Mol. Biol. Cell 22, 782-794. https://doi.org/10.1091/mbc.E10-11-0879
  6. Byrne, C., M. Tainsky, and E. Fuchs. 1994. Programming gene expression in developing epidermis. Development 120, 2369-2383.
  7. Cao, M., R. Cabrera, Y. Xu, C. Liu, and D. Nelson. 2011. Different radiosensitivity of CD4(+)CD25(+) regulatory T cells and effector T cells to low dose gamma irradiation in vitro. Int. J. Radiat. Biol. 87, 71-80. https://doi.org/10.3109/09553002.2010.518208
  8. Chapoval, S., P. Dasgupta, N. J. Dorsey, and A. D. Keegan. 2010. Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J. Leukoc. Biol. 87, 1011-1018. https://doi.org/10.1189/jlb.1209772
  9. Coulombe, P. A. and M. B. Omary. 2002. 'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments. Curr. Opin. Cell Biol. 14, 110-122. https://doi.org/10.1016/S0955-0674(01)00301-5
  10. Cua, D. J. and C. M. Tato. 2010. Innate IL-17-producing cells: the sentinels of the immune system. Nat. Rev. Immunol. 10, 479-489. https://doi.org/10.1038/nri2800
  11. Dong, C. 2008. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 8, 337-348. https://doi.org/10.1038/nri2295
  12. Hirahara, K., K. Ghoreschi, A. Laurence, X. P. Yang, Y. Kanno, and J. J. O'Shea. 2010. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 21, 425-434. https://doi.org/10.1016/j.cytogfr.2010.10.006
  13. Huber, S., N. Gagliani, E. Esplugues, W. O'Connor, Jr., F. J. Huber, A. Chaudhry, M. Kamanaka, Y. Kobayashi, C. J. Booth, A. Y. Rudensky, M. G. Roncarolo, M. Battaglia, and R. A. Flavell. 2011. Th17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3(-) and Foxp3(+) Regulatory CD4(+) T Cells in an Interleukin-10-Dependent Manner. Immunity 34, 554-565. https://doi.org/10.1016/j.immuni.2011.01.020
  14. Ito, Y., P. Sarkar, Q. Mi, N. Wu, P. Bringas, Jr., Y. Liu, S. Reddy, R. Maxson, C. Deng, and Y. Chai. 2001. Overexpression of Smad2 reveals its concerted action with Smad4 in regulating TGF-beta-mediated epidermal homeostasis. Dev. Biol. 236, 181-194. https://doi.org/10.1006/dbio.2001.0332
  15. Liu, C., J. Lin, L. Zhao, Y. Yang, F. Gao, B. Li, J. Cui, and J. Cai. 2011. Gamma-ray Irradiation Impairs Dendritic Cell Migration to CCL19 by Down-regulation of CCR7 and Induction of Cell Apoptosis. Int. J. Biol. Sci. 7, 168-179.
  16. Lorimore, S. A., P. J. Coates, G. E. Scobie, G. Milne, and E. G. Wright. 2001. Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects?. Oncogene 20, 7085-7095. https://doi.org/10.1038/sj.onc.1204903
  17. Maeng, H. G., D. N. Kim, S. K. Cho, J. H. Cha, T. Y. Kim, Y. S. Lee, D. K. Choi, J. H. Lee, M. J. Cho, H. J. Kwon, and S. K. Lee. 2006. Altered immune cell proportions in the radiodermatitis induced hairless mice-1 (HR-1). J. Radiat. Res. (Tokyo) 47, 9-17. https://doi.org/10.1269/jrr.47.9
  18. Martin, M., J. Lefaix, and S. Delanian. 2000. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target?. Int. J. Radiat. Oncol. Biol. Phys. 47, 277-290. https://doi.org/10.1016/S0360-3016(00)00435-1
  19. Mills, K. H. 2004. Regulatory T cells: friend or foe in immunity to infection?. Nat. Rev. Immunol. 4, 841-855. https://doi.org/10.1038/nri1485
  20. Miossec, P., T. Korn, and V. K. Kuchroo. 2009. Interleukin-17 and type 17 helper T cells. N. Engl. J. Med. 361, 888-898. https://doi.org/10.1056/NEJMra0707449
  21. Morris, R. J., Y. Liu, L. Marles, Z. Yang, C. Trempus, S. Li, J. S. Lin, J. A. Sawicki, and G. Cotsarelis. 2004. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411-417. https://doi.org/10.1038/nbt950
  22. Murai, M., O. Turovskaya, G. Kim, R. Madan, C. L. Karp, H. Cheroutre, and M. Kronenberg. 2009. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 10, 1178-1184. https://doi.org/10.1038/ni.1791
  23. Nakajima, K., T. Kanda, M. Takaishi, T. Shiga, K. Miyoshi, H. Nakajima, R. Kamijima, M. Tarutani, J. M. Benson, M. M. Elloso, L. L. Gutshall, M. F. Naso, Y. Iwakura, J. DiGiovanni, and S. Sano. 2011. Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model. J. Immunol. 186, 4481-4489. https://doi.org/10.4049/jimmunol.1000148
  24. Romano, R. A., B. Birkaya, and S. Sinha. 2007. A functional enhancer of keratin14 is a direct transcriptional target of deltaNp63. J. Invest. Dermatol. 127, 1175-1186. https://doi.org/10.1038/sj.jid.5700652
  25. Said, E. A., F. P. Dupuy, L. Trautmann, Y. Zhang, Y. Shi, M. El-Far, B. J. Hill, A. Noto, P. Ancuta, Y. Peretz, S. G. Fonseca, J. Van Grevenynghe, M. R. Boulassel, J. Bruneau, N. H. Shoukry, J. P. Routy, D. C. Douek, E. K. Haddad, and R. P. Sekaly. 2010. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat. Med. 16, 452-459. https://doi.org/10.1038/nm.2106
  26. Sauter, B., M. L. Albert, L. Francisco, M. Larsson, S. Somersan, and N. Bhardwaj. 2000. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423-434. https://doi.org/10.1084/jem.191.3.423
  27. Schweizer, J., P. E. Bowden, P. A. Coulombe, L. Langbein, E. B. Lane, T. M. Magin, L. Maltais, M. B. Omary, D. A. Parry, M. A. Rogers, and M. W. Wright. 2006. New consensus nomenclature for mammalian keratins. J. Cell. Biol. 174, 169-174. https://doi.org/10.1083/jcb.200603161
  28. Shen, J., S. Bao, and V. E. Reeve. 1999. Modulation of IL-10, IL-12, and IFN-gamma in the epidermis of hairless mice by UVA (320-400 nm) and UVB (280-320 nm) radiation. J. Invest. Dermatol. 113, 1059-1064. https://doi.org/10.1046/j.1523-1747.1999.00782.x
  29. Shevach, E. M. 2009. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636-645. https://doi.org/10.1016/j.immuni.2009.04.010
  30. Tokura, Y., T. Mori, and R. Hino. 2010. Psoriasis and other Th17-mediated skin diseases. J. UOEH. 32, 317-328.
  31. Tucker, R. F., G. D. Shipley, H. L. Moses, and R. W. Holley. 1984. Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226, 705-707. https://doi.org/10.1126/science.6093254
  32. Tumbar, T., G. Guasch, V. Greco, C. Blanpain, W. E. Lowry, M. Rendl, and E. Fuchs. 2004. Defining the epithelial stem cell niche in skin. Science 303, 359-363. https://doi.org/10.1126/science.1092436
  33. Wang, X. J., D. A. Greenhalgh, J. R. Bickenbach, A. Jiang, D. S. Bundman, T. Krieg, R. Derynck, and D. R. Roop. 1997. Expression of a dominant-negative type II transforming growth factor beta (TGF-beta) receptor in the epidermis of transgenic mice blocks TGF-beta-mediated growth inhibition. Proc. Natl. Acad. Sci. USA 94, 2386-2391. https://doi.org/10.1073/pnas.94.6.2386
  34. Weiss, E., A. J. Mamelak, S. La Morgia, B. Wang, C. Feliciani, A. Tulli, and D. N. Sauder. 2004. The role of interleukin 10 in the pathogenesis and potential treatment of skin diseases. J. Am. Acad. Dermatol. 50, 657-675; quiz 676-658. https://doi.org/10.1016/j.jaad.2003.11.075
  35. Wing, K., Z. Fehervari, and S. Sakaguchi. 2006. Emerging possibilities in the development and function of regulatory T cells. Int. Immunol. 18, 991-1000. https://doi.org/10.1093/intimm/dxl044
  36. Yang, L., L. Wang, and X. Yang. 2009. Disruption of Smad4 in mouse epidermis leads to depletion of follicle stem cells. Mol. Biol. Cell 20, 882-890. https://doi.org/10.1091/mbc.E08-07-0731