TSHβ剪切体在碘过量和甲状腺球蛋白引发NOD鼠自身免疫性甲状腺炎的表达
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摘要
目的
已知除了垂体,免疫系统也能产生TSH。最近科学家发现一种骨髓造血细胞可以表达TSHβ剪切体并可迁移到甲状腺组织表达该物质。SHβ剪切体在垂体、骨髓和甲状腺都有表达,但脾作为机体重要的免疫器官,是否表达这一剪切体尚未证实,且该剪切体的病理生理学意义尚且不清。因此我们要确认脾组织是否表达TSHβ剪切体；通过检测TSHβ剪切体在碘过量和甲状腺球蛋白诱发的自身免疫性甲状腺炎中小鼠不同器官表达的变化,探讨发生甲状腺炎时,TSHβ剪切体对甲状腺功能发挥的作用,初步了解TSHβ剪切体与甲状腺炎发病的关系。以便更深入研究TSHP剪切体在下丘脑-垂体-甲状腺轴以及在免疫-内分泌相互作用的中的具体作用和机制。
方法
本实验首先选择20只雌性自身免疫性疾病易感的NOD小鼠,7-8周龄,随机分为4组,每组5只。分别为：对照组(C)：饮用去离子水；碘过量组(HI)：饮用0.05%NaI水；TG组(TG)：饮用去离子水,8周龄时给予每只鼠0.1mgTG皮下免疫,11周龄、15周龄加强免疫两次；碘过量+TG组(HI+TG)：饮0.05%NaI水,TG免疫同上。取动物全血,采用RIA法和ELISA法分别检测小鼠血清中甲状腺激素和促甲状腺素水平。
然后对垂体和脾组织进行TSHβ免疫荧光染色,观察TSHβ阳性细胞在脾的分布。使用PCR技术对TSHβ剪切体在NOD小鼠垂体、骨髓、脾与甲状腺组织中表达进行检测,并对脾组织该基因的扩增产物进行测序。用SYBR GREEN实时荧光定量PCR法分析不同处理因素下TSHP剪切体基因mRNA表达。
结果
TG组与C组比较血清T4水平和TSH水平都增加。C组T4水平为(36.43±3.87) nmol/L, TSH水平为(5.55±0.28) ng/mL。TG组血清T4水平为(69.70±16.45) nmol/L (P<0.05)和TSH水平为(8.44±0.71) ng/mL (P<0.01)。HI组和HI+TG组TT4水平较C组无统计学差异,而TSH水平较C组升高,分别为(6.98±0.27) ng/mL (P<0.05)和(9.12±0.36) ng/mL (P<0.01)。
脾组织TSHβ阳性细胞主要位于边缘区,生发中心有少量阳性细胞,但不能确认是天然型TSHβ还是TSHβ剪接体；垂体可见大量TSHβ阳性细胞。
RT-PCR技术显示骨髓、垂体、甲状腺和脾都表达TSHβ剪接体,但是除垂体外其他组织都不表达自然型TSHβ。
TG组骨髓TSHβ剪接体表达(0.026±0.010)较C组(0.014±0.007)增加(P<0.05),垂体和甲状腺TSHβ剪接体表达与C组比无明显差异,垂体自然型TSHβ表达与C组比也无明显差异。
HI组骨髓TSHβ剪接体表达与C组比较无差异；HI组垂体TSHβ剪接体表达与C组比较明显增加(P<0.01),HI组为(0.038±0.010),C组为(0.015±0.007)；HI组甲状腺TSHβ剪切体表达较C组增加(P<0.05),HI组为(0.036±0.007),C组为(0.017±0.003)；垂体自然型TSHβ表达(0.013±0.003)与C组(0.006±0.000)比增加(P<0.01)。
HI+TG组只有垂体自然型TSHβ(0.015±0.004)与C组比较,表达有增加(P<0.01)。
各处理组脾组织TSHβ剪切体表达未做出结果。
结论
NOD小鼠脾脏作为机体重要的免疫器官也可以表达TSHβ剪切体。TG免疫可使血中TSH水平升高,与源于骨髓细胞分泌的TSHβ剪切体表达有关,骨髓TSHβ剪切体的表达可能不受血中T4的负反馈调节；碘过量使T4水平下降,垂体中天然型TSHβmRNA的表达升高,其变化符合HPT轴的反馈学说,而垂体TSHβ剪切体表达的调控还有待于进一步研究验证；碘过量组与TG免疫组甲状腺TSHβ剪切体表达不一致,提示与碘过量诱发的EAT是以细胞免疫为主的炎症,所造成的炎症反应和组织破坏程度较TG免疫更为严重,导致向甲状腺迁移的分泌TSHβ剪切体的骨髓细胞增加有关。
Objective:As we all know in addition to pituitary, immune system can produce TSH. Scientists recently found a set of resident intrathyroidal bone marrow-derived hematopoietic cells which can express a novel TSHP splice variant. The TSHP splice variant gene was expressed in the pituitary, bone marrow and the thyroid. Spleen is an important immune organ which expresses TSHβ, we need to confirm it is native TSHP or TSHβsplice variant. We detected the expression of TSHP splice variant in different organs on autoimmune thyroiditis induced by iodine excess and thyroglobulin in NOD mice, to explore the function of TSHP splice variant in infection-or inflammatory-related thyroid disorders.
Methods:Twenty Non-obese diabetic mice,7-8 weeks old, female, were randomly divided randomly into four groups:control group (C):drank deionized water; iodine excess group (HI):drank 0.05% NaI water; TG group (TG):drank deionized water, immunized with 0.1mg TG to each mouse by subcutaneously injection at 8 weeks old and enhanced at 11 and 15 weeks old; iodine excess+TG group (HI+TG):drank 0.05% NaI water, TG immunization was the same as TG group. Then collected blood samples, RIA and ELISA were used respectively to detect T4 and TSH level in serum.
For observing distribution of TSHP positive cells, TSHβimmunofluorescence staining was used on pituitary, and spleen. The expression of TSHP splice variant mRNA were detected by real time PCR in different organs and the amplified gene of spleen was sequenced. SYBR Green real-time PCR was used to detect the levels of TSHP splice variant genes in different organs.
Results:TG group had a higher level of T4 and TSH compared to C group. The level of T4 and TSH in C group were separately (36.43±3.87) nmol/L and (5.55±0.28) ng/mL, while the level of T4 and TSH in TG group were(69.70±16.45)nmol/L(P<0.05) and (8.44±0.71)ng/mL (P<0.01).
The level of T4 in HI group and HI+TG group had no significant different compared to C group. But HI group and HI+TG group had higher level of TSH than C group, were (6.98±0.27)ng/mL (P<0.05) and (9.12±0.36)ng/mL(P<0.01) separately.
In spleen, majority of TSHβ+ cells were localized in the marginal zones, few of which localized in germinal center. In pituitary, there were large number of TSHβ+ cells.
RT-PCR showed that TSHP splice variant was not only expressed in the pituitary, bone marrow and thyroid but also in the spleen. Native TSHP was only expressed in pituitary. In TG group, expression of TSHP splice variant in bone marrow (0.026±0.010) (P<0.05) increased compared to C group (0.014±0.007), while pituitary and thyroid had no higher expression of TSHβsplice variant than C group. Native TSHβin pituitary had no significant different either. In HI group, expression of TSHP splice variant in bone marrow did not changed significantly, but expression of TSHP splice variant in pituitary(0.038±0.010)(P<0.01) and thyroid(0.036±0.007)(P<0.05) were higher than C group(0.017±0.003). Native TSHP in pituitary was higher (0.013±0.003) (P<0.01). In HI+TG group only the expression of native TSHP in pituitary increased (0.015±0.004) (P<0.01). TSHp splice variant expression in spleen had no significant result.
Conclusions:Spleen as an important immune organ in NOD mice can express TSHP splice variant. Increased level of TSH in TG group had something to do with the expression of bone marrow TSHP splice variant. Its production and secretion may not be subject to the negative feedback regulation of circulating T4. In TG group, pituitary expression of native TSHβmRNA meet the HPT axis feedback theory, but the regulation of expression of TSHβsplice variant in pituitary needs further research. Expression of TSHP splice variant of thyroid in HI group and TG group was different, suggesting that excess iodine-induced EAT is a cellular immune-based inflammation, the inflammatory response and tissue damage are more serious than the TG immunity, leading to more bone marrow cells that express TSHP splice variant migrate to the thyroid.
已知除了垂体,免疫系统也能产生TSH。最近科学家发现一种骨髓造血细胞可以表达TSHβ剪切体并可迁移到甲状腺组织表达该物质。SHβ剪切体在垂体、骨髓和甲状腺都有表达,但脾作为机体重要的免疫器官,是否表达这一剪切体尚未证实,且该剪切体的病理生理学意义尚且不清。因此我们要确认脾组织是否表达TSHβ剪切体；通过检测TSHβ剪切体在碘过量和甲状腺球蛋白诱发的自身免疫性甲状腺炎中小鼠不同器官表达的变化,探讨发生甲状腺炎时,TSHβ剪切体对甲状腺功能发挥的作用,初步了解TSHβ剪切体与甲状腺炎发病的关系。以便更深入研究TSHP剪切体在下丘脑-垂体-甲状腺轴以及在免疫-内分泌相互作用的中的具体作用和机制。
方法
本实验首先选择20只雌性自身免疫性疾病易感的NOD小鼠,7-8周龄,随机分为4组,每组5只。分别为：对照组(C)：饮用去离子水；碘过量组(HI)：饮用0.05%NaI水；TG组(TG)：饮用去离子水,8周龄时给予每只鼠0.1mgTG皮下免疫,11周龄、15周龄加强免疫两次；碘过量+TG组(HI+TG)：饮0.05%NaI水,TG免疫同上。取动物全血,采用RIA法和ELISA法分别检测小鼠血清中甲状腺激素和促甲状腺素水平。
然后对垂体和脾组织进行TSHβ免疫荧光染色,观察TSHβ阳性细胞在脾的分布。使用PCR技术对TSHβ剪切体在NOD小鼠垂体、骨髓、脾与甲状腺组织中表达进行检测,并对脾组织该基因的扩增产物进行测序。用SYBR GREEN实时荧光定量PCR法分析不同处理因素下TSHP剪切体基因mRNA表达。
结果
TG组与C组比较血清T4水平和TSH水平都增加。C组T4水平为(36.43±3.87) nmol/L, TSH水平为(5.55±0.28) ng/mL。TG组血清T4水平为(69.70±16.45) nmol/L (P<0.05)和TSH水平为(8.44±0.71) ng/mL (P<0.01)。HI组和HI+TG组TT4水平较C组无统计学差异,而TSH水平较C组升高,分别为(6.98±0.27) ng/mL (P<0.05)和(9.12±0.36) ng/mL (P<0.01)。
脾组织TSHβ阳性细胞主要位于边缘区,生发中心有少量阳性细胞,但不能确认是天然型TSHβ还是TSHβ剪接体；垂体可见大量TSHβ阳性细胞。
RT-PCR技术显示骨髓、垂体、甲状腺和脾都表达TSHβ剪接体,但是除垂体外其他组织都不表达自然型TSHβ。
TG组骨髓TSHβ剪接体表达(0.026±0.010)较C组(0.014±0.007)增加(P<0.05),垂体和甲状腺TSHβ剪接体表达与C组比无明显差异,垂体自然型TSHβ表达与C组比也无明显差异。
HI组骨髓TSHβ剪接体表达与C组比较无差异；HI组垂体TSHβ剪接体表达与C组比较明显增加(P<0.01),HI组为(0.038±0.010),C组为(0.015±0.007)；HI组甲状腺TSHβ剪切体表达较C组增加(P<0.05),HI组为(0.036±0.007),C组为(0.017±0.003)；垂体自然型TSHβ表达(0.013±0.003)与C组(0.006±0.000)比增加(P<0.01)。
HI+TG组只有垂体自然型TSHβ(0.015±0.004)与C组比较,表达有增加(P<0.01)。
各处理组脾组织TSHβ剪切体表达未做出结果。
结论
NOD小鼠脾脏作为机体重要的免疫器官也可以表达TSHβ剪切体。TG免疫可使血中TSH水平升高,与源于骨髓细胞分泌的TSHβ剪切体表达有关,骨髓TSHβ剪切体的表达可能不受血中T4的负反馈调节；碘过量使T4水平下降,垂体中天然型TSHβmRNA的表达升高,其变化符合HPT轴的反馈学说,而垂体TSHβ剪切体表达的调控还有待于进一步研究验证；碘过量组与TG免疫组甲状腺TSHβ剪切体表达不一致,提示与碘过量诱发的EAT是以细胞免疫为主的炎症,所造成的炎症反应和组织破坏程度较TG免疫更为严重,导致向甲状腺迁移的分泌TSHβ剪切体的骨髓细胞增加有关。
Objective:As we all know in addition to pituitary, immune system can produce TSH. Scientists recently found a set of resident intrathyroidal bone marrow-derived hematopoietic cells which can express a novel TSHP splice variant. The TSHP splice variant gene was expressed in the pituitary, bone marrow and the thyroid. Spleen is an important immune organ which expresses TSHβ, we need to confirm it is native TSHP or TSHβsplice variant. We detected the expression of TSHP splice variant in different organs on autoimmune thyroiditis induced by iodine excess and thyroglobulin in NOD mice, to explore the function of TSHP splice variant in infection-or inflammatory-related thyroid disorders.
Methods:Twenty Non-obese diabetic mice,7-8 weeks old, female, were randomly divided randomly into four groups:control group (C):drank deionized water; iodine excess group (HI):drank 0.05% NaI water; TG group (TG):drank deionized water, immunized with 0.1mg TG to each mouse by subcutaneously injection at 8 weeks old and enhanced at 11 and 15 weeks old; iodine excess+TG group (HI+TG):drank 0.05% NaI water, TG immunization was the same as TG group. Then collected blood samples, RIA and ELISA were used respectively to detect T4 and TSH level in serum.
For observing distribution of TSHP positive cells, TSHβimmunofluorescence staining was used on pituitary, and spleen. The expression of TSHP splice variant mRNA were detected by real time PCR in different organs and the amplified gene of spleen was sequenced. SYBR Green real-time PCR was used to detect the levels of TSHP splice variant genes in different organs.
Results:TG group had a higher level of T4 and TSH compared to C group. The level of T4 and TSH in C group were separately (36.43±3.87) nmol/L and (5.55±0.28) ng/mL, while the level of T4 and TSH in TG group were(69.70±16.45)nmol/L(P<0.05) and (8.44±0.71)ng/mL (P<0.01).
The level of T4 in HI group and HI+TG group had no significant different compared to C group. But HI group and HI+TG group had higher level of TSH than C group, were (6.98±0.27)ng/mL (P<0.05) and (9.12±0.36)ng/mL(P<0.01) separately.
In spleen, majority of TSHβ+ cells were localized in the marginal zones, few of which localized in germinal center. In pituitary, there were large number of TSHβ+ cells.
RT-PCR showed that TSHP splice variant was not only expressed in the pituitary, bone marrow and thyroid but also in the spleen. Native TSHP was only expressed in pituitary. In TG group, expression of TSHP splice variant in bone marrow (0.026±0.010) (P<0.05) increased compared to C group (0.014±0.007), while pituitary and thyroid had no higher expression of TSHβsplice variant than C group. Native TSHβin pituitary had no significant different either. In HI group, expression of TSHP splice variant in bone marrow did not changed significantly, but expression of TSHP splice variant in pituitary(0.038±0.010)(P<0.01) and thyroid(0.036±0.007)(P<0.05) were higher than C group(0.017±0.003). Native TSHP in pituitary was higher (0.013±0.003) (P<0.01). In HI+TG group only the expression of native TSHP in pituitary increased (0.015±0.004) (P<0.01). TSHp splice variant expression in spleen had no significant result.
Conclusions:Spleen as an important immune organ in NOD mice can express TSHP splice variant. Increased level of TSH in TG group had something to do with the expression of bone marrow TSHP splice variant. Its production and secretion may not be subject to the negative feedback regulation of circulating T4. In TG group, pituitary expression of native TSHβmRNA meet the HPT axis feedback theory, but the regulation of expression of TSHβsplice variant in pituitary needs further research. Expression of TSHP splice variant of thyroid in HI group and TG group was different, suggesting that excess iodine-induced EAT is a cellular immune-based inflammation, the inflammatory response and tissue damage are more serious than the TG immunity, leading to more bone marrow cells that express TSHP splice variant migrate to the thyroid.
引文
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[35]王永臣,陈豪敏,王传刚,等.黄河下游滩区发现地方性高碘甲肿流行[J].中国地方病防治杂志.1993,8(4)：223.
[36]Barin JG, Talor MV, Sharma RB, et al. Iodination of murine thytoglobulin enhances autoimmune reactivity in the NOD.H2h4 mouse[J]. Clinical and Experimental Immunology,2005,142(2):251-259.
[37]Fountoulakis S, Philippou G, Tsatsoulis A. The Role of iodine in the evolution of thyroid disease in Greece:from endemic goiter to thyroid autoimmunity[J]. Hormones,2007,6(1):25-35.
[38]Moij P, de Wit HJ, Drexhage HA. An excess of dietary iodine accelerates the development of a thyroid-associated lymphoid tissue in autoimmune prone BB rats[J]. Clin Immunol Immunopathol,1993,69:189-198.
[39]Moij P, Simons PJ, de Haan-Meulman M, et al. Effect of thyroid hormones and other iodinated compounds on the transition of monocytes into veiled/dendritic cells: role of granulocyte-macrophage colony-stimulating factor, tumour-necrosis factor-alpha and interleukin-6[J]. Endocrinol,1994,140:503-512.
[40]Su He Wang, Ronald J. Koenig. A locally secreted thyrotropin variant may regulate thyroid function in thyroid inflammatory disorders[J].Thyroid,2009, 19(1):5-6.
[41]De Groot LJ. Dangerous dogmas in medicine:the nonthyrodial illness syndrome[J]. Endocrinol Metab,1999,84:151-164.
[42]De Miguel M, Fernandez-Santos JM, Utrilla JC, et al. Thyrotropin-releasing hormone receptor expression in thyroid follicular cells:a new paracrine role of C-cells[J]? Histol Histopathol,2005,20(3):713-8.
[43]Pazos-Moura CC, Ortiga-Carvalho TM, Gaspar de Moura E.The autocrine/paracrine regulation of thyrotropin secretion[J]. Thyroid,2003, 13(2):167-75.
[1]Szkudlinski M, Fremont V, Ronin C, et al. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships[J]. Physiol Rev, 2002,82:473-502.
[2]Kelley G.. Peripheral metabolism of thyroid hormones:a review[J]. Altern Med Rev,2000,5:306-33.
[3]Smith EM, Phan M, Kruger TE, et al. Human lymphocyte production of immunoreactive thyrotropin[J]. Proc Natl Acad Sci USA,1982,80:6010-6013.
[4]Kruger TE, Blalock JE. Cellular requirements for thyrotropin enhancement of in vitro antibody production[J]. Immunol,1986,137:197-200.
[5]Kruger TE, Smith EM, Harbour DV, et al.Thyrotropin:an endogenous regulator of the in vitro immune response[J]. Immunol,1989,142:744-747.
[6]Harbour DV, Kruger TE, Coppenhaver D, et al. Differential expression and regulation of thyrotropin (TSH) in T cell lines[J]. Mol Cell Endocrinol,1989, 64:229-241.
[7]Bagriacik EU, Zhou Q, Wang H-C, et al. Rapid and transient reduction in circulating thyroid hormones following systemic antigen priming:implications for functional collaboration between dendritic cells and thyroid[J]. Cell Immunol,2001, 212:92-100.
[8]Klein JR, Wang H-C. Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells:potential for immune-endocrine interactions in thyroid homeostasis[J]. Exp Biol,2004,207:55-65.
[9]Wang H-C, Dragoo J, Zhou Q, et al. An intrinsic thyrotropinmediated pathway of TNF-a production by bone marrow cells[J]. Blood,2003,101:119-123.
[10]Zhou Q, Wang H-C, Klein JR. Characterization of a novel anti-mouse thyrotropin monoclonal antibody[J]. Hybrid Hybridomics,2002,21:75-79.
[11]Wang H-C, Whetsell M, Klein JR. Local hormone networks and intestinal T cell homeostasis[J]. Science,1997,275:1937-1939.
[12]Scofield VL, Montufar-Solis D, Cheng E, et al. Intestinal TSH production is localized in villus "hotblocks" and is coupled to IL-7 production:evidence for involvement of TSH during acute virus infection[J]. Immunol Lett,2005,99:36-44.
[13]Saito H, Kanamori Y, Takemori T, et al. Generation of intestinal T cells from progenitors residing in gut cryptopatches[J]. Science,1998,280:275-278.
[14]Wang J, Klein JR. Thymus-neuroendocrine interactions in extrathymic T cell development[J]. Science,1994,265:1860-1862.
[15]Wang J, Klein JR. Hormonal regulation of extrathymic gut T cell development: involvement of thyroid stimulating hormone[J]. Cell Immunol,1995,161:299-302.
[16]Coutelier JP, Kehrl JH, Bellur SS, et al. Binding and functional effects of thyroid stimulating hormone to human immune cells[J]. Clin Immunol,1990,10:204-210.
[17]Bagriacik EU, Klein JR. The thyrotropin (thyroid stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD43RBhigh lymph node T cells:functional role of thyroid stimulating hormone during immune activation[J]. Immunol,2000,164:6158-6165.
[18]Kruger TE. Immunomodulation of peripheral lymphocytes by hormones of the hypothalamus-pituitary-thyroid axis[J]. Adv Neuroimmunol,1996,6:387-395.
[19]Fabris N, Mochegiani E, Provinciali M. Pituitary-thyroid axis and immune system:a reciprocal neuroendocrine-immune interaction[J]. Horm Res,1995, 43:29-38.
[20]Blalock JE, Johnson HM, Smith EM, et al. Enhancement of the in vitro antibody response by thyrotropin[J]. Biochem Biophys Res Comm,1984,25:30-34.
[21]Provinciali M, Di Stefano G, Fabris N. Improvement in the proliferative capacity and natural killer cell activity of murine spleen lymphocytes by thyrotropin[J]. Immunopharmacol,1992,14:865-870.
[22]Whetsell M, Bagriacik EU, Seetharamaiah GS, et al. Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties[J]. Cell Immunol,1999,192:159-166.
[23]Foster MP, Montecino-Rodriguez E, Dorshkind K. Proliferation of bone marrow pro-B cells is dependent on stimulation by the pituitary/thyroid axis[J]. Immunol, 1999,163:5883-5889.
[24]Dorshkind K, Horseman ND. The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency[J]. Endocrine Rev,2005,21:292-312.
[25]Aprin C, Philgren M, Fraichard A, et al. Effects of T3Ral and T3Ra2 gene deletion on T and B lymphocyte development[J]. Immunol,2000,164:152-160.
[26]Beigneux AP, Moser AH, Shigenaga JK, et al. Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver[J]. Physiol Endocrinol Metab,2003,284:E228-E236.
[27]De Groot LJ. Dangerous dogmas in medicine:the nonthyrodial illness syndrome[J]. Clin Endocrinol Metab,1999,84:151-164.
[28]Papanicolaou DA. Euthyroid sick syndrome and the role of cytokines[J]. Rev Endocr Metab Disord,2000,1:43-48.
[29]Inan M, Koyuncu A, Aydin C, et al. Thyroid hormone supplementation in sepsis: an experimental study[J]. Surg Today,2003,33:24-29.
[30]Klemperer JD. Thyroid hormone and cardiac surgery[J]. Thyroid,2002, 12:517-521.
[31]Brierre S, Kumari R, Deboisblanc BP. The endocrine system during sepsis[J]. Med Sci,2004,328:238-247.
[32]Larsen PR, Davies TF, Schumberger MJ, et al. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In:Plonsky KS, Ed. Williams Textbook of Endocrinology (10th ed.) [J]. Philadelphia:WB Saunders,2002, pp350.
[33]Fakete C, Gereben B, Doleschall M, et al. Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus:implications for the nonthyroidal illness syndrome[J]. Endocrinology,2004,145:1649-1655.
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[13]Wang HC, Dragoo J, Zhou Q, et al. An intrinsic thyrotropin-mediated pathway of TNF-alpha production by bone marrow cells[J]. Blood,2003,101:119-123.
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[36]Barin JG, Talor MV, Sharma RB, et al. Iodination of murine thytoglobulin enhances autoimmune reactivity in the NOD.H2h4 mouse[J]. Clinical and Experimental Immunology,2005,142(2):251-259.
[37]Fountoulakis S, Philippou G, Tsatsoulis A. The Role of iodine in the evolution of thyroid disease in Greece:from endemic goiter to thyroid autoimmunity[J]. Hormones,2007,6(1):25-35.
[38]Moij P, de Wit HJ, Drexhage HA. An excess of dietary iodine accelerates the development of a thyroid-associated lymphoid tissue in autoimmune prone BB rats[J]. Clin Immunol Immunopathol,1993,69:189-198.
[39]Moij P, Simons PJ, de Haan-Meulman M, et al. Effect of thyroid hormones and other iodinated compounds on the transition of monocytes into veiled/dendritic cells: role of granulocyte-macrophage colony-stimulating factor, tumour-necrosis factor-alpha and interleukin-6[J]. Endocrinol,1994,140:503-512.
[40]Su He Wang, Ronald J. Koenig. A locally secreted thyrotropin variant may regulate thyroid function in thyroid inflammatory disorders[J].Thyroid,2009, 19(1):5-6.
[41]De Groot LJ. Dangerous dogmas in medicine:the nonthyrodial illness syndrome[J]. Endocrinol Metab,1999,84:151-164.
[42]De Miguel M, Fernandez-Santos JM, Utrilla JC, et al. Thyrotropin-releasing hormone receptor expression in thyroid follicular cells:a new paracrine role of C-cells[J]? Histol Histopathol,2005,20(3):713-8.
[43]Pazos-Moura CC, Ortiga-Carvalho TM, Gaspar de Moura E.The autocrine/paracrine regulation of thyrotropin secretion[J]. Thyroid,2003, 13(2):167-75.
[1]Szkudlinski M, Fremont V, Ronin C, et al. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships[J]. Physiol Rev, 2002,82:473-502.
[2]Kelley G.. Peripheral metabolism of thyroid hormones:a review[J]. Altern Med Rev,2000,5:306-33.
[3]Smith EM, Phan M, Kruger TE, et al. Human lymphocyte production of immunoreactive thyrotropin[J]. Proc Natl Acad Sci USA,1982,80:6010-6013.
[4]Kruger TE, Blalock JE. Cellular requirements for thyrotropin enhancement of in vitro antibody production[J]. Immunol,1986,137:197-200.
[5]Kruger TE, Smith EM, Harbour DV, et al.Thyrotropin:an endogenous regulator of the in vitro immune response[J]. Immunol,1989,142:744-747.
[6]Harbour DV, Kruger TE, Coppenhaver D, et al. Differential expression and regulation of thyrotropin (TSH) in T cell lines[J]. Mol Cell Endocrinol,1989, 64:229-241.
[7]Bagriacik EU, Zhou Q, Wang H-C, et al. Rapid and transient reduction in circulating thyroid hormones following systemic antigen priming:implications for functional collaboration between dendritic cells and thyroid[J]. Cell Immunol,2001, 212:92-100.
[8]Klein JR, Wang H-C. Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells:potential for immune-endocrine interactions in thyroid homeostasis[J]. Exp Biol,2004,207:55-65.
[9]Wang H-C, Dragoo J, Zhou Q, et al. An intrinsic thyrotropinmediated pathway of TNF-a production by bone marrow cells[J]. Blood,2003,101:119-123.
[10]Zhou Q, Wang H-C, Klein JR. Characterization of a novel anti-mouse thyrotropin monoclonal antibody[J]. Hybrid Hybridomics,2002,21:75-79.
[11]Wang H-C, Whetsell M, Klein JR. Local hormone networks and intestinal T cell homeostasis[J]. Science,1997,275:1937-1939.
[12]Scofield VL, Montufar-Solis D, Cheng E, et al. Intestinal TSH production is localized in villus "hotblocks" and is coupled to IL-7 production:evidence for involvement of TSH during acute virus infection[J]. Immunol Lett,2005,99:36-44.
[13]Saito H, Kanamori Y, Takemori T, et al. Generation of intestinal T cells from progenitors residing in gut cryptopatches[J]. Science,1998,280:275-278.
[14]Wang J, Klein JR. Thymus-neuroendocrine interactions in extrathymic T cell development[J]. Science,1994,265:1860-1862.
[15]Wang J, Klein JR. Hormonal regulation of extrathymic gut T cell development: involvement of thyroid stimulating hormone[J]. Cell Immunol,1995,161:299-302.
[16]Coutelier JP, Kehrl JH, Bellur SS, et al. Binding and functional effects of thyroid stimulating hormone to human immune cells[J]. Clin Immunol,1990,10:204-210.
[17]Bagriacik EU, Klein JR. The thyrotropin (thyroid stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD43RBhigh lymph node T cells:functional role of thyroid stimulating hormone during immune activation[J]. Immunol,2000,164:6158-6165.
[18]Kruger TE. Immunomodulation of peripheral lymphocytes by hormones of the hypothalamus-pituitary-thyroid axis[J]. Adv Neuroimmunol,1996,6:387-395.
[19]Fabris N, Mochegiani E, Provinciali M. Pituitary-thyroid axis and immune system:a reciprocal neuroendocrine-immune interaction[J]. Horm Res,1995, 43:29-38.
[20]Blalock JE, Johnson HM, Smith EM, et al. Enhancement of the in vitro antibody response by thyrotropin[J]. Biochem Biophys Res Comm,1984,25:30-34.
[21]Provinciali M, Di Stefano G, Fabris N. Improvement in the proliferative capacity and natural killer cell activity of murine spleen lymphocytes by thyrotropin[J]. Immunopharmacol,1992,14:865-870.
[22]Whetsell M, Bagriacik EU, Seetharamaiah GS, et al. Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties[J]. Cell Immunol,1999,192:159-166.
[23]Foster MP, Montecino-Rodriguez E, Dorshkind K. Proliferation of bone marrow pro-B cells is dependent on stimulation by the pituitary/thyroid axis[J]. Immunol, 1999,163:5883-5889.
[24]Dorshkind K, Horseman ND. The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency[J]. Endocrine Rev,2005,21:292-312.
[25]Aprin C, Philgren M, Fraichard A, et al. Effects of T3Ral and T3Ra2 gene deletion on T and B lymphocyte development[J]. Immunol,2000,164:152-160.
[26]Beigneux AP, Moser AH, Shigenaga JK, et al. Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver[J]. Physiol Endocrinol Metab,2003,284:E228-E236.
[27]De Groot LJ. Dangerous dogmas in medicine:the nonthyrodial illness syndrome[J]. Clin Endocrinol Metab,1999,84:151-164.
[28]Papanicolaou DA. Euthyroid sick syndrome and the role of cytokines[J]. Rev Endocr Metab Disord,2000,1:43-48.
[29]Inan M, Koyuncu A, Aydin C, et al. Thyroid hormone supplementation in sepsis: an experimental study[J]. Surg Today,2003,33:24-29.
[30]Klemperer JD. Thyroid hormone and cardiac surgery[J]. Thyroid,2002, 12:517-521.
[31]Brierre S, Kumari R, Deboisblanc BP. The endocrine system during sepsis[J]. Med Sci,2004,328:238-247.
[32]Larsen PR, Davies TF, Schumberger MJ, et al. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In:Plonsky KS, Ed. Williams Textbook of Endocrinology (10th ed.) [J]. Philadelphia:WB Saunders,2002, pp350.
[33]Fakete C, Gereben B, Doleschall M, et al. Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus:implications for the nonthyroidal illness syndrome[J]. Endocrinology,2004,145:1649-1655.
[34]Fakete C, Singru PS, Sarkar S, et al. Ascending brainstem pathways are not involved in lipopolysaccharide-induced suppression of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus[J]. Endocrinology,2005, 146:1357-1363.
[35]Pang XP, Hershman JM, Chung M, et al. Characterization of tumor necrosis factor-alpha receptors by thyrotropin[J]. Endocrinology,1989,125:1783-1788.
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