Clinical and Experimental Reproductive Medicine

  • 제36권2호
  • /
  • Pages.89-100
  • /
  • 2009
  • /
  • 2233-8233(pISSN)
  • /
  • 2233-8241(eISSN)
대한생식의학회 (The Korean Society for Reproductive Medicine)
권호 표지

에스트로겐이 T 림프구 면역기능에 미치는 영향

The Influence of Estrogen on the Immunologic Function of T Lymphocytes

  • 전성욱 (서울대학교 의과대학 산부인과학교실) ;
  • 정경천 (서울대학교 의과대학 병리학교실) ;
  • 구승엽 (서울대학교 의과대학 산부인과학교실)
  • Chun, Sung-Wook (Department of Obstetrics and Gynecology, Seoul National University College of Medicine) ;
  • Chun, Kyung-Chun (Department of Pathology, Seoul National University College of Medicine) ;
  • Ku, Seung-Yup (Department of Obstetrics and Gynecology, Seoul National University College of Medicine)
  • 발행 : 2009.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

SLE 등의 자가면역질환 병인론에 있어서 $CD4^+$ T 조력 림프구 (T helper cell)의 기능과 항상성 조절의 이상이 중요하다는 것은 알려진 사실이지만 $CD4^+$ T 조력 림프구 (T helper cell)의 발달과 기능에 대한 성호르몬의 정확한 역할에 대하여는 아직 확립되어 있지 않은 실정이다. 에스트로겐의 $CD4^+$ T 림프구에 대한 여러 방면의 작용에 대한 결과는 에스트로겐 매개 신호가 전달되는 정황에 매우 의존적이라고 할 수 있으며, 또한 에스트로겐이 B 림프구와 항원발현세포들 같이 T 림프구 기능을 변화시킬 수 있는 다른 분획 세포들의 기능에 대해서도 영향을 미칠 수 있다는 사실을 고려한다면, 에스트로겐이 $CD4^+$ T 림프구매개반응에 미치는 작용은 매우 복잡하다고 할 수 있다. 현재로선 이런 과정들과 관련된 에스트로겐의 정확한 기전에 대한 연구 성과는 현재로선 아직걸음마 단계에 지나지 않는다고 볼 수 있다. 일부 분자학적 표적들의 발견에도 불구하고 ER-$\alpha$와 ER-$\beta$, 또는 이런 표적들의 조절에 대한 유전자적 또는 비유전자적 경로의 상대적 역할에 대해서는 현재로선 알려진 바가 많지 않은 것 또한 사실이며, T 림프구 자체의 미세 환경과 ER 매개 전사반응에 영향을 미칠 수 있는 방법 역시 아직까진 알려진 바가 없다. 따라서 에스트로겐의 $CD4^+$ T 림프구에 대한 다각적 영향을 규명하는 데 있어 이런 경로들에 대한 보다 체계적이고 상세한 연구가 반드시 필요하다. 최근 골다공증의 병인에 있어 에스트로겐에 의한 TNF 및 RANK-RANKL계 억제에 대해 연구가 심도 있게 진행됨으로써 결과적으로 다른 시토카인과 면역세포들에 대한 영향이 간접적으로 규명되고 있는 점은 매우 고무적인 현상이라고 여겨진다. 이러한 연구들은 추후 에스트로겐의 면역 및 염증체계에 대한 특징적 작용을 규명하는데 있어서 밑거름이 될 수 있을 것이다. 나아가 호르몬 자체, 또는 SERM 같은 준호르몬제제들이 면역계에 미치는 영향을 분자학적으로 규명함으로써 향후 이러한 지식들이 또한 류마티스성 자가면역질환이나 만성염증성질환, 또는 전신성 감염질환에 있어 면역글로불린이나 기타 다른 기존 치료 약제들을 대체 보완할 수 있는 호르몬 치료로 이어질 수 있는 결정적인 단서를 제공할 수 있을 것이라 기대할 수 있을 것이다.

키워드

참고문헌

  1. Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007; 28: 521-74 https://doi.org/10.1210/er.2007-0001
  2. Pernis AB. Estrogen and CD4+ T cells. Curr Opin Rheumatol 2007; 19: 414-20 https://doi.org/10.1097/BOR.0b013e328277ef2a
  3. Buyon JP. The effects of pregnancy on autoimmune diseases. J Leukoc Biol 1998; 63: 281-7
  4. Grimaldi CM. Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol 2006; 18: 456-61 https://doi.org/10.1097/01.bor.0000240354.37927.dd
  5. Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. 7th ed. Philadelphia: Lipincott Williams and Wilkins, 2005; 45-57
  6. Matthews J, Gustafsson JA. Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv 2003; 3: 281-92 https://doi.org/10.1124/mi.3.5.281
  7. Edwards DP. Regulation of signal transduction pathways by estrogen and progesterone. Annu Rev Physiol 2005; 67:335-376 https://doi.org/10.1146/annurev.physiol.67.040403.120151
  8. Hall JM, Couse JF, Korach KS. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 2001; 276: 36869-72 https://doi.org/10.1074/jbc.R100029200
  9. Gruber CJ, Gruber DM, Gruber IM, Wieser F, Huber JC. Anatomy of the estrogen response element. Trends Endocrinol Metab 2004; 15: 73-8 https://doi.org/10.1016/j.tem.2004.01.008
  10. Edwards DP. The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 2000; 5: 307-24 https://doi.org/10.1023/A:1009503029176
  11. Driggers PH, Segars JH. Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling. Trends Endocrinol Metab 2002; 13: 422-7 https://doi.org/10.1016/S1043-2760(02)00634-3
  12. Song RX, Zhang Z, Santen RJ. Estrogen rapid action via protein complex formation involving ERalpha and Src. Trends Endocrinol Metab 2005; 16: 347-53 https://doi.org/10.1016/j.tem.2005.06.010
  13. Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cellpopulations. Immunol Lett 2005; 97:107-13 https://doi.org/10.1016/j.imlet.2004.10.007
  14. Shim GJ, Gherman D, Kim HJ, et al. Differential expression of oestrogen receptors in human secondary lymphoid tissues. J Pathol 2006; 208: 408-14 https://doi.org/10.1002/path.1883
  15. Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, et al. Human estrogen receptor betagene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997; 82: 4258-65 https://doi.org/10.1210/jc.82.12.4258
  16. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997; 138: 863-70 https://doi.org/10.1210/en.138.3.863
  17. Kassi EN, Vlachoyiannopoulos PG, Moutsopoulos HM, Sekeris CE, Moutsatsou P. Molecular analysis of estrogen receptor alpha and beta in lupus patients. Eur J Clin Invest 2001; 31: 86-93 https://doi.org/10.1046/j.1365-2362.2001.00762.x
  18. Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI. Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998; 25: 1305-12
  19. Rider V, Li X, Peterson G, Kimler BF, Abdou NI. Differential expression of estrogen receptors in women with systemic lupus erythematosus. J Rheumatol 2006; 33: 1093-101
  20. Okasha SA, Ryu S, Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS. Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus. Toxicology 2001; 163: 49-62 https://doi.org/10.1016/S0300-483X(01)00374-2
  21. Staples JE, Gasiewicz TA, Fiore NC, Lubahn DB, Korach KS, Silverstone AE. Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J Immunol 1999; 163: 4168-74
  22. Kendall MD, Clarke AG. The thymus in the mouse changes its activity during pregnancy: a study of the microenvironment. J Anat 2000; 197 (Pt 3): 393-411 https://doi.org/10.1046/j.1469-7580.2000.19730393.x
  23. Yao G, Hou Y. Thymic atrophy via estrogen-induced apoptosis is related to Fas/FasL pathway. Int Immunopharmacol 2004;4: 213-21 https://doi.org/10.1016/j.intimp.2003.12.005
  24. Ryan MR, Shepherd R, Leavey JK, Gao Y, Grassi F, Schnell FJ, et al. An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency. Proc Natl Acad Sci U S A 2005; 102: 16735-40 https://doi.org/10.1073/pnas.0505168102
  25. Mor G, Munoz A, Redlinger R Jr, Silva I, Song J, Lim C, et al. The role of the Fas/Fas ligand system in estrogen-induced thymic alteration. AmJ Reprod Immunol 2001; 46: 298-307 https://doi.org/10.1034/j.1600-0897.2001.d01-16.x
  26. Do Y, Ryu S, Nagarkatti M, Nagarkatti PS. Role of death receptor pathway in estradiol-induced T-cell apoptosis in vivo. Toxicol Sci 2002; 70: 63-72 https://doi.org/10.1093/toxsci/70.1.63
  27. Selvaraj V, Bunick D, Finnigan-Bunick C, Johnson RW, Wang H, Liu L, et al. Gene expression profiling of 17beta-estradiol and genistein effects on mouse thymus. Toxicol Sci 2005; 87:97-112 https://doi.org/10.1093/toxsci/kfi219
  28. Ladi E, Yin X, Chtanova T, Robey EA. Thymic microenvironments for T cell differentiation and selection. Nat Immunol 2006; 7: 338-43 https://doi.org/10.1038/ni1323
  29. Erlandsson MC, Ohlsson C, Gustafsson JA, Carlsten H. Role of oestrogen receptors alpha and beta in immune organ development and in oestrogenmediated effects on thymus. Immunology 2001; 103: 17-25 https://doi.org/10.1046/j.1365-2567.2001.01212.x
  30. Erlandsson MC, Gomori E, Taube M, Carlsten H. Effects of raloxifene, a selective estrogen receptor modulator, on thymus, T cell reactivity, and inflammation in mice. Cell Immunol 2000; 205: 103-9 https://doi.org/10.1006/cimm.2000.1719
  31. Grimaldi CM, Hicks R, Diamond B. B cell selection and susceptibility to autoimmunity. J Immunol 2005; 174: 1775-81
  32. Bottomly K. A functional dichotomy in CD4$\rho$ T lymphocytes. Immunol Today 1988; 9: 268-74 https://doi.org/10.1016/0167-5699(88)91308-4
  33. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348-57
  34. Romagnani S. Human TH1 and TH2: doubt no more. Immunol Today 1991; 12: 256-7 https://doi.org/10.1016/0167-5699(91)90120-I
  35. Szabo S, Sullivan B, Peng S, Glimcher L. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21: 713-58 https://doi.org/10.1146/annurev.immunol.21.120601.140942
  36. Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A, et al. Estradiol enhances primary antigenspecific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells. Eur J Immunol 2003; 33: 512-21 https://doi.org/10.1002/immu.200310027
  37. Bao M, Yang Y, Jun HS, Yoon JW. Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol 2002;168: 5369-75
  38. Bebo BF Jr, Fyfe-Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H. Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol 2001; 166: 2080-9
  39. Krishnan L, Guilbert LJ, Russell AS, Wegmann TG, Mosmann TR, Belosevic M, et al. Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigenspecific IFN-gamma response and increased production of T helper 2 cytokines. J Immunol 1996; 156:644-52
  40. Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFNgamma promoter. J Immunol 1991; 146: 4362-7
  41. Gonsky R, Deem RL, Bream JH. An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells. Genes Immun 2006; 7: 342-51 https://doi.org/10.1038/sj.gene.6364305
  42. Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 2005;5: 521-31 https://doi.org/10.1038/nri1648
  43. Karpuzoglu E, Phillips RA, Gogal RM Jr, Ansar Ahmed S. IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12. Mol Immunol 2007; 44: 1808-14 https://doi.org/10.1016/j.molimm.2006.08.005
  44. Lengi AJ, Phillips RA, Karpuzoglu E, Ahmed SA. 17betaestradiol downregulates interferon regulatory factor-1 in murine splenocytes. J Mol Endocrinol 2006; 37: 421-32 https://doi.org/10.1677/jme.1.02122
  45. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, Estes DM. Estrogen receptor $\alpha$ (ER$\alpha$) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17$\beta$-estradiol acts through ERα to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol 2005: 175: 5716-23
  46. Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, et al. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol 2004: 173: 2227-30
  47. Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 2004; 22: 307-28 https://doi.org/10.1146/annurev.immunol.22.012703.104533
  48. Fanzo JC, Yang W, Jang SY, Gupta S, Chen Q, Siddiq A, et al. Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest 2006;116: 703-14 https://doi.org/10.1172/JCI24096
  49. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6:1133-41 https://doi.org/10.1038/ni1261
  50. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007: 13: 139-45 https://doi.org/10.1038/nm1551
  51. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 2003; 171: 6173-7
  52. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem 2003; 278: 17036-43 https://doi.org/10.1074/jbc.M210429200
  53. Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss:an inflammatory tale. J Clin Invest 2006; 116: 1186-94 https://doi.org/10.1172/JCI28550
  54. Pacifici R. Editorial: Cytokines, Estrogen, and Postmenopausal Osteoporosis-The Second Decade Endocrinology 1998; 139:2659-61 https://doi.org/10.1210/en.139.6.2659
  55. Roodman GD. Advances in bone biology: The osteoclast. Endocr Rev 1996; 17: 308-32
  56. Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, et al. Proc Natl Acad Sci U S A. Up-regulation of TNFproducing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. 2001;20; 98(24): 13960-5
  57. Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 2000; 50: 184-95 https://doi.org/10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H
  58. Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol 2003; 66: 1403-8 https://doi.org/10.1016/S0006-2952(03)00490-8
  59. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Wood ring J, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-$\alpha$. J Clin Invest 2000;106: 1229-37 https://doi.org/10.1172/JCI11066
  60. Roggia C, Tamone C, Cenci S, Pacifici R, Isaia GC. Role of TNF-$\alpha$ producing T-cells in bone loss induced by estrogen deficiency. Minerva Med 2004; 95: 125-32
  61. Jones DH, Kong YY, Penninger JM. Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 2002; 61 Suppl 2: ii32-9 https://doi.org/10.1136/ard.61.suppl_2.ii32
  62. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 1990; 345: 442-4 https://doi.org/10.1038/345442a0
  63. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 1999; 397: 315-23 https://doi.org/10.1038/16852
  64. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14363-7 https://doi.org/10.1074/jbc.273.23.14363
  65. Simonet WS, Lacey DL, Dunstan CR, Kelly M,Chang MS, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319 https://doi.org/10.1016/S0092-8674(00)80209-3
  66. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-8 https://doi.org/10.1101/gad.12.9.1260
  67. Lengi AJ, Phillips RA, Karpuzoglu E, Ahmed SA. Estrogen selectively regulates chemokines in murine splenocytes. J Leukoc Biol 2007; 81: 1065-74 https://doi.org/10.1189/jlb.0606391
  68. Perez de Lema G, Maier H, Nieto E, Vielhauer V, Luckow B, Mampaso F, et al. Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis. J Am Soc Nephrol 2001; 12: 1369-82
  69. Anders HJ, Belemezova E, Eis V, Segerer S, Vielhauer V, Perez de Lema G, et al. Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J Am Soc Nephrol 2004; 15: 1504-13 https://doi.org/10.1097/01.ASN.0000130082.67775.60
  70. Acconcia F, Barnes CJ, Kumar R. Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells. Endocrinology 2006; 147: 1203-12 https://doi.org/10.1210/en.2005-1293
  71. Gupta S, Lee A, Hu C, Fanzo J, Goldberg I, Cattoretti G, et al. Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system. Hum Immunol 2003; 64: 389-401 https://doi.org/10.1016/S0198-8859(03)00024-7
  72. Gupta S, Fanzo J, Hu C, Lee A, Goldberg I, Cattoretti G, et al. T cell receptor engagement leads to the recruitment of IBP, a novel guanine nucleotide exchange factor, to the immunological synapse. J Biol Chem 2003; 278: 43451-9