Biomedical subjects

B Y Cho

Publications and source records attributed to B Y Cho.

At least 19 recordsLinked to original sources

PubMed2005

p66Shc expression in proliferating thyroid cells is regulated by thyrotropin receptor signaling.

It is almost unanimously accepted that thyrocyte proliferation is synergistically activated by TSH and insulin/IGF-I. Moreover, it was recently suggested that p66Shc, which is an adaptor molecule of the IGF-I receptor, might play a critical role in this synergistic effect. In this study, we undertook to confirm the role and the mechanism underlying the regulation of p66Shc expression via TSH receptor in thyrocytes. We have found that p66Shc expression is elevated in proliferating human thyroid tissues, including adenomatous goiter, adenoma, Graves' disease, and thyroid cancer, but not in normal thyroid. Among growth factors, TSH increased p66Shc expression both in vivo and in vitro; however, IGF-I, epidermal growth factor, or insulin did not. TSH and Graves' Ig increased the p66Shc expression via the TSH receptor-G(s)-cAMP pathway. However, interestingly, IGF-I or epidermal growth factor increased the tyrosine phosphorylations of p66Shc, and this was enhanced by TSH pretreatment. A similar synergism was observed during the DNA synthesis. When we measured the p66Shc levels induced by individual Igs from 130 patients with Graves' disease, TSH receptor stimulating activity and goiter size showed a weak correlation. We conclude that the expression of p66Shc is regulated by signaling through the TSH receptor in proliferating thyroid cells and that p66Shc appears to be an important mediator of the synergistic effect between TSH and IGF-I with respect to thyrocyte proliferation. Moreover, we suggest that TSH potentiates the regulatory effect of IGF-I on thyrocyte growth, at least in part, by increasing the expression of p66Shc.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation.

OBJECTIVE: This study was designed to investigate whether an elevated serum antithyroglobulin antibody (TgAb) reflects cancer recurrence in thyroglobulin (Tg)-undetectable patients with differentiated thyroid carcinoma (DTC) after thyroid ablation. DESIGN: We measured serum TgAb level and evaluated the disease status in 226 DTC patients who had undergone remnant ablation and showed an undetectable Tg result as assessed by immunoradiometric assay. MEASUREMENTS: Radioligand assay of TgAb was performed. Recurrence was assessed by 131I scan, 18F-fluorodeoxyglucose positron emission tomography, sonography, computed tomography, or by surgical operation. RESULTS: Fifty-one patients (22.6%) of the Tg-undetectable patients showed positive TgAb, and 25 (49.0%) of these were confirmed with recurrence. The recurrence rate of TgAb-positive patients was higher than that of TgAb-negative patients (3.4%; P < 0.0001). During follow-up, 73.1% of the disease-free patients showed spontaneously decreased TgAb levels. A total of 71.4% of patients with recurrent cancer, who showed responses to surgical operation or radio-iodine treatment, also showed a decreased TgAb level. CONCLUSIONS: Persistently elevated TgAb levels appear to serve as a useful marker for recurrent or persistent DTC in patients with undetectable serum Tg results. Thus, the routine measurement of TgAb in such patient populations may be indicated.

Adolescent↗

PubMed2001

Homogeneous fluorescent derivatization of large proteins.

A method of homogeneously derivatizing large proteins for highly sensitive analysis is described. Homogeneity of the derivative was realized by tagging all the free amino groups of proteins. With this method, alpha-chymotrypsinogen A, ovalbumin and bovine serum albumin were derivatized with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC). Prior to the derivatization, all the proteins were reduced and alkylated. After reacting the resulting unfolded proteins with excessive amounts of AQC, the samples were analyzed with matrix assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) to determine the derivatization degree. The results indicated that all three proteins had been, or had almost been, fully derivatized. HPLC and CE were used for characterizing these protein derivatives. Under the optimized fluorescence detection conditions, the detectability of the tagged proteins was 2400-6200 times better than that detected at UV 280 nm, 170-300 times better than detected at UV 214 nm, and 150-420 times better than measured with their native fluorescence.

Electrophoresis, Capillary↗

PubMed2001

F-18-fluorodeoxyglucose positron emission tomography as a presurgical evaluation modality for I-131 scan-negative thyroid carcinoma patients with local recurrence in cervical lymph nodes.

BACKGROUND: F-18-labeled fluorodeoxyglucose-positron emission tomography (FDG-PET) has a supplementary role in localizing recurrent sites of differentiated thyroid carcinoma. We evaluated whether FDG-PET is feasible as a presurgical evaluation modality for I-131 scan-negative thyroid carcinoma patients. METHODS: Preoperative FDG-PET results were compared with the pathologic findings of lymph nodes specimens of 22 papillary thyroid patients. All patients had thyroidectomy and I-131 ablation therapy beforehand and showed negative I-131 scans on follow-up studies. RESULTS: In 85 cervical lymph node groups dissected, 56 lymph node groups revealed metastasis. The sensitivity and specificity of FDG PET for metastasis were 80% (45 of 56) and 83% (24 of 29), respectively. Among the pathologically positive 33 lymph nodes with normal size(< or =1 cm), FDG-PET detected 23 nodes. Serum thyroglobulin levels were elevated in 12 patients (sensitivity, 55%). CONCLUSION: FDG-PET accurately detected the recurred cervical lymph nodes of differentiated thyroid carcinoma patients who showed negative I-131 scan. FDG-PET is suitable for the presurgical evaluation of these patients.

Adult↗

PubMed2001

Relationship between various surrogate indices of insulin resistance and mitochondrial DNA content in the peripheral blood of 18 healthy volunteers.

Mutations or deletions of mitochondrial DNA (mtDNA) are associated with diabetes mellitus. In this study, we investigated the relationships between the mtDNA content in peripheral blood and surrogate indices of insulin resistance in 18 healthy young women (mean age 20.8 +/- 1.5 years). The mtDNA content was significantly correlated with the area under the curve of insulin during an oral glucose tolerance test (r = -0.622), the homeostasis model assessment for insulin resistance (r = -0.616), the ratio of fasting glucose to insulin concentration (r = 0.586) and the fasting insulin level (r = -0.552). Further study is warranted to elucidate the mechanism by which the mtDNA content is associated with insulin resistance.

Journal Article↗

PubMed2001

Diagnostic value of serum IGF-I and IGFBP-3 in growth hormone disorders in adults.

OBJECTIVE: To investigate the diagnostic value of serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) measurements in adult patients with acromegaly and GH deficiency (GHD). METHODS: Serum IGF-I and IGFBP-3 levels were measured in 39 active acromegalic patients, 34 adult patients with GHD and 150 healthy adults. Disease activity in patients with acromegaly was confirmed by nadir GH levels during an oral glucose tolerance test (OGTT). Among patients with acromegaly, 15 had not been treated previously and 24 had been treated but not cured. GHD in adults was diagnosed by an insulin tolerance test (ITT). Among patients with GHD, 15 were aged 20-40 years (9 men and 6 women) and 19 were aged over 40 years (9 men and 10 women). One hundred and fifty healthy subjects were recruited as a control group. To compare the individual serum IGF-I and IGFBP-3 levels of patients with the results of the gold standard, we calculated age- and sex-corrected standard deviation scores (SDS) for individual IGF-I and IGFBP-3 levels. The sensitivities of serum IGF-I and IGFBP-3 measurements for the disease diagnosis were analyzed using the mean +/- 2 SD of the values of healthy control subjects as a diagnostic cutoff, defining 95% specificity. RESULTS: The mean IGF-I and IGFBP-3 SDS levels were significantly higher in active acromegalic patients, both untreated and treated but not cured, than in the control subjects (p < 0.05). The sensitivities of serum IGF-I and IGFBP-3 measurements for the diagnosis of acromegaly were 97.4 and 81.8%, respectively. In untreated patients with acromegaly, the sensitivities of serum IGF-I and IGFBP-3 measurements for the diagnosis of disease were 100 and 100%, while these were 95.8 and 72.7% in treated patients with acromegaly. In adult patients with GHD, the mean IGF-I and IGFBP-3 SDS were significantly lower than those of the control subjects (IGF-I, -2.2 +/- 0.8 vs. 0.0 +/- 1.0 SDS, p < 0.0001); IGFBP-3, -1.7 +/- 1.2 vs. 0.0 +/- 1.0 SDS, p < 0.0001), but there was a considerable overlap between GHD in adults and the controls. In all patients with GHD, the sensitivities of serum IGF-I and IGFBP-3 measurements were 64.7 and 52.9%, respectively. In the group of women aged 20-40 years, the sensitivity of IGF-I measurement for the diagnosis of GHD was 100%, although the number of patients was only 6. CONCLUSION: Both serum IGF-I and IGFBP-3 measurements are comparable to an oral glucose tolerance test in patients with untreated acromegaly, but in acromegalic patients that have undergone surgery and/or radiotherapy, serum IGF-I is more valuable for determining disease activity than serum IGFBP-3. Serum IGF-I and IGFBP-3 measurements are not valuable for the diagnosis of GHD in adults, but in women aged 20-40 years serum IGF-I measurement appears to be useful in the diagnosis of GHD.

Acromegaly↗

PubMed2001

Prevalence of Gs alpha mutations in Korean patients with pituitary adenomas.

The reported frequencies of Gs alpha mutations (gsp mutations) in growth hormone (GH)-secreting pituitary adenomas are variable (ranging from 4.4 to 43%), and the presence of these mutations in the other pituitary adenomas is still a matter of controversy. Previous clinical and biochemical analyses of patients with GH-secreting pituitary adenomas and gsp mutations produced conflicting results and did not demonstrate obvious characteristics. Therefore, we investigated the prevalence of gsp mutations in Korean patients with pituitary adenomas and elucidated the characteristics of these patients. Forty-four GH-secreting adenomas, 7 prolactin (PRL)-secreting adenomas and 32 clinically non-functioning adenomas were examined for the presence of point mutations in codon 201 and 227 of the Gs alpha gene using a nested PCR and direct sequencing of DNA extracted from fresh tissue or paraffin-embedded pituitary adenoma samples. Seven of the 44 GH-secreting pituitary adenomas had point mutations at codon 201 or 227; of these, five mutations were in codon 201 and two were in codon 227. In patients with gsp mutations, mean tumor size was significantly smaller than in patients without gsp mutations (15.9+/-8.7 mm vs. 24.9+/-14.9 mm, P<0.05). Age, sex, basal GH levels, GH response to oral glucose loading, GH response to octreotide and surgical outcome were not different in the two groups. One of the 32 clinically non-functioning pituitary adenomas had a point mutation at codon 201; none of the seven prolactinomas had these mutations. These results show that gsp mutations are not rare in Korean acromegalic patients and mean tumor size is significantly smaller in acromegalic patients with gsp mutations. Our results also confirm the low frequency of gsp mutations in clinically non-functioning pituitary adenomas and the absence of gsp mutations in prolactinoma.

Acromegaly↗

PubMed2001

Clinical significance of classification of Graves' disease according to the characteristics of TSH receptor antibodies.

BACKGROUND: It has been widely accepted that the epitope(s) and/or functional characteristics of thyrotropin receptor antibodies (TSHRAb) from Graves' patients are heterogenous among patients. However, the clinical significance of such heterogeneity has not been systematically evaluated yet. We were to elucidate and find the clinical significance of heterogeneity for TSH receptor antibodies in Graves' disease. METHODS: We measured stimulating TSHRAb (TSAb) activities using CHO-hTSHR cells, FRTL-5 cells and chimeric receptor expressing cells (Mc1 + 2 and Mc2), specific blocking TSHRAb (TSBAb) activities using Mc2 cells and TBII activities using porcine thyroid membrane in 136 patients with untreated hyperthyroid Graves' disease. RESULTS: Based on various TSHRAb activities from each patient, the patients could be categorized into 7 subgroups by cluster analysis; 1) Group 1 (n = 41) was characterized by moderate TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, typical TSAb epitope, rare blocking antibodies and high TBII activities. 2) Group 2 (n = 16) was characterized by the presence of blocking TSHRAb in most patients, albeit the other characteristics were the same as those in Group 1. 3) Group 3 (n = 19) patients had low TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, seldom had blocking TSHRAb, but they had high TBII activities. 4) Group 4 (n = 30) could be categorized as 'mild disease' group, as they had low activities in all kinds of TSHRAb assay and had low antimicrosomal antibody activities. 5) Group 5 (n = 14) was characterized by moderate TSAb activities with atypical epitope(s), rare blocking TSHRAb and moderate TBII activities. 6) Group 6 (n = 10) patients had very high TSAb activities with typical epitopes, seldom blocking TSHRAb and low TBII activities. 7) Group 7 (n = 6) was characterized by very high TSAb activities with atypical epitopes and high TBII activities. Pretreatment serum thyroid hormone level was low only in group 4 patients compared to the other 6 groups (p < 0.05). The size of goiter was significantly larger in those in group 1 and group 3 (p < 0.05) compared to the other 5 groups. The prevalence of clinically significant ophthalmopathy was higher in group 2 patients than the other 6 groups (50% vs. 27.5%, p = 0.06). Among 6 kinds of TSHRAb activities, only the blocking TSHRAb activity was significantly associated with the presence of ophthalmopathy in multivariate analysis. CONCLUSION: These results suggest that the differences in epitopes for TSAb or the presence of blocking TSHRAb is not a major factor in determining the degree of thyrotoxicosis in Graves' disease. Although the pathogenic mechanism is not clear yet, we suggest that patients with ophthalmopathy have different TSHRAb repertoire from those without ophthalmopathy in Graves' disease.

Adolescent↗

PubMed2001

Relationship between expression of the sodium/iodide symporter and 131I uptake in recurrent lesions of differentiated thyroid carcinoma.

The sodium/iodide symporter (NIS) is known to be responsible for the active accumulation of iodide within the thyroid gland. We evaluated the relationship between the expression of NIS in primary or lymph node lesions and iodine-131 uptake in recurrent lesions of differentiated thyroid cancer. In 67 patients with differentiated thyroid cancer (5 follicular and 62 papillary carcinomas), the expression of NIS was analysed by immunohistochemical staining using polyclonal antibodies against human NIS. We used paraffin block tissues of primary tumours or metastatic lesions, and also assessed 131I uptake in recurrent lesions of thyroid cancer on post-operative 131I whole-body scan. Immunohistochemical staining was positive in 22 patients (32.8%), including 2 of 5 follicular and 20 of 62 papillary carcinomas. Recurrence was confirmed in 40 patients pathologically or clinically by serum thyroglobulin, 131I scan, fluorine-18 fluorodeoxyglucose positron emission tomography and/or computed tomography. Among these 40 patients, 28 showed positive uptake on 131I scan. Fourteen tumour specimens out of 28 (50%) were positive by NIS immunohistochemical staining. The remaining 12 patients with recurrent cancer showed negative 131I scans, and all specimens were negative by NIS immunohistochemical staining. Thus, NIS immunohistochemical staining predicted 131I uptake in recurrent cancer with a 100% positive predictive value and a 46.2% negative predictive value. There was no difference in the positivity of NIS according to the site of recurrence on 131I scan. Outcome of 131I therapy could be assessed in 22 of the 28 patients who showed 131I uptake in recurrent lesions. Patients with positive NIS immunostaining responded to 131I therapy better than did patients with negative immunostaining (P<0.05). In conclusion, NIS immunohistochemical staining showed a high positive predictive value in predicting iodine uptake. Positive immunohistochemical staining of human NIS in primary or lymph node lesions may predict 131I accumulation and effectiveness of 131I therapy in recurrent lesions.

Adenocarcinoma, Follicular↗

PubMed2000

Effect of exercise on the mitochondrial DNA content of peripheral blood in healthy women.

Exercise decreases insulin resistance and increases maximal exercise capacity as estimated from maximal oxygen uptake (VO2max). Recent reports have demonstrated that the mitochondrial DNA (mtDNA) content of blood is correlated with VO2max in healthy subjects (mean age 31 years) and is inversely correlated with insulin resistance parameters. The aim of this study was to determine the effect of regular exercise on the mtDNA content in the peripheral blood of 16 healthy young women of mean age 24.8 (SD 6.2) years and 14 healthy older women of mean age 66.7 (SD 5.8) years. The exercise programme lasted for 10 weeks and consisted of three sessions a week, each of 1 h and aiming to attain 60%-80% of VO2max. The mtDNA content of peripheral blood was measured by competitive polymerase chain reaction. The VO2max had significantly increased following the exercise programme [from 33.1 (SD 3.4) to 35.2 (SD 3.4) ml x kg(-1) min(-1) in the young and from 24.3 (SD 5.3) to 30.3 (SD 7.3) ml x kg(-1) x min(-1) in the older women, both P < 0.05]. Exercise decreased systolic blood pressure, and concentrations of triglyceride, low density lipoprotein-cholesterol (LDL-C), glucose and insulin in the blood of the young and of total cholesterol, LDL-C and glucose in that of the older women. High density lipoprotein-cholesterol (HDL-C) in the young women was increased by exercise. The mtDNA content significantly increased following the exercise programme in both groups [from 27.1 (SD 17.9) to 52.7 (SD 44.6) amol x 5 ng(-1) genomic DNA in the young and from 15.3 (SD 10.2) to 32.1 (SD 30.0) amol x 5 ng(-1) genomic DNA in the older women, both P < 0.05]. There was a significant positive correlation between the change in mtDNA content and the change in VO2max (r = 0.74 in the young and r = 0.71 in the older women, both P < 0.01). In conclusion, 10 weeks of moderate intensity, regular exercise increased the mtDNA content in peripheral blood and decreased insulin resistance parameters. This data suggests that increase in the mtDNA content may be associated with increased insulin sensitivity.

Adolescent↗

PubMed2000

Polymorphism in the promoter and exon 1 of the cytotoxic T lymphocyte antigen-4 gene associated with autoimmune thyroid disease in Koreans.

The objective of this study was to examine the polymorphism in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and its relationship with autoimmune thyroid disease in Koreans. Polymorphism in the promoter and exon 1 of CTLA-4, clinical symptoms of disease and thyrotropin receptor antibody (TSHRAb) characteristics were analyzed. Polymorphism was detected using restriction fragment length polymorphism and polymerase chain reaction amplification of genomic DNA. All subjects were Korean (97 Graves' disease, 110 Hashimoto's thyroiditis, and 199 normal controls). Graves' patients had significantly more G allele in exon 1 and C allele in the promoter than controls. When the exon 1 genotype was GG, the frequency of CC genotype in the promoter was higher. Allele frequencies in CTLA-4 did not differ from controls in patients with Hashimoto's thyroiditis. In Graves' patients, there were significant differences between genotypic groups in serum triiodothyronine (T3) levels and the presence of ophthalmopathy. However, TSHRAbs and other clinical characteristics were not significantly different. In conclusion, the CTLA-4 G allele in exon 1 and C allele in the promoter may confer genetic susceptibility to Graves' disease in Koreans. These two polymorphisms are additional and dependent genetic risk markers that help to characterize risk alleles within CTLA-4 gene.

Abatacept↗

PubMed2000

The prevalence and clinical significance of blocking thyrotropin receptor antibodies in untreated hyperthyroid Graves' disease.

The goal of this study was to evaluate the clinical significance of the blocking thyrotropin receptor antibodies (TSHRAb) in Graves' disease. The amount of blocking and stimulating TSHRAb were measured in 200 patients with untreated hyperthyroid Graves' disease using several cell lines carrying different TSHR chimera. Stimulating TSHRAb were measured in Chinese hamster ovary (CHO) cells with wild-type human TSHR (CHO-hTSHR) or a TSHR chimera with residues 90-165 (Mc2) or 8-165 (Mc1+2) substituted by equivalent residues of rat luteinizing hormone/chorionic gonadotrophin (LH/CG) receptor or in FRTL-5 cells. Blocking TSHRAb were measured in Mc2 cells. The activities of different TSHRAb were assessed and clinical features were compared to patients who were positive or negative for blocking TSHRAb antibodies. Blocking TSHRAbs were detected in 18.5% of patients (37/200) with hyperthyroid Graves' disease. Patients with blocking antibodies had significantly lower mean stimulating TSHRAb activities than those without blocking antibodies in wild-type CHO-hTSHR cells (301 +/- 179 vs. 446% +/- 537%, p = 0.005). Mean stimulating TSHRAb activities measured by FRTL-5, Mc1+2, or Mc2 cells and mean thyrotropin receptor inhibitor immunoglobulin (TBII) activities were not different between the two groups. The patients with blocking antibodies were not different from those without blocking antibodies in age, gender ratio, initial serum free thyroxine (T4) levels, or goiter size. However, the prevalence of exophthalmos was higher (35.1% vs. 17.5%, p = 0.024) in the patients with blocking antibodies than those without. In summary, the presence of blocking TSHRAb is not rare in patients with hyperthyroid Graves' disease when measured with chimeric receptor expressing cells. Blocking TSHRAb in Graves' sera do not strongly antagonize the action of stimulating TSHRAb in vivo, but could be a major factor responsible for underestimation of stimulating TSHRAb activities measured by CHO-hTSHR. The association of blocking TSHRAb with ophthalmopathy suggests that the TSHRAb repertoire of Graves' patients is different in those who do and who do not have ophthalmopathy.

Adult↗

PubMed2000

Dissociation between plasma adrenocorticotropin and serum cortisol level during the early postoperative period after gastrectomy.

We demonstrated the dissociation between plasma adrenocorticotropin (ACTH) and serum cortisol levels during the early recovery period after radical gastrectomy in 9 of 31 patients with gastric adenocarcinoma. Patients with the dissociation between plasma ACTH and serum cortisol levels (DAC) showed a sustained elevation of serum cortisol level on the first or second postoperative day, while the plasma ACTH level returned to its preoperative state. These patients also had more advanced cancers (p < 0.05) and suffered from more postoperative complications (p < 0.05) than those without DAC. In these patients with DAC, serum cortisol and interleukin (IL)-6 levels remained higher on the second postoperative day than in those of the patients without DAC (21.80 +/- 1.57 vs. 13.68 +/- 0.72 microg/dl, p < 0.001, and 74.31 +/- 15.65 vs. 18.75 +/- 3.14 pg/ml, p < 0.001, respectively). On the second postoperative day, serum IL-6 levels showed a significant correlation with serum cortisol levels in all patients (r = 0.511, p < 0.01). These results suggest that the DAC during the early postoperative period after radical gastrectomy is associated with advanced stage of cancer and postoperative complication, and that the increased serum IL-6 level is at least in part responsible for maintaining the elevated serum cortisol.

Adenocarcinoma↗

PubMed2000

Thyrotropin induces SOCS-1 (suppressor of cytokine signaling-1) and SOCS-3 in FRTL-5 thyroid cells.

TSH has multiple physiological roles: it is required for growth, differentiation, and function of the thyroid gland, and it regulates transcription of interferon-gamma (IFN-gamma)-responsive genes in thyrocytes, including genes for the major histocompatibility complex and intercellular adhesion molecule-1. This report demonstrates that TSH induces the expression of suppressor of cytokine signaling (SOCS)-1 and -3 proteins and alters the phosphorylation state of signal transducer and activator of transcription (STAT) proteins STAT1 and STAT3. The expression of SOCS-1 and SOCS-3 and the phosphorylation state of STAT1 and STAT3 were examined after treatment with TSH or IFN-gamma in either TSH-sensitive FRTL-5 thyroid cells or TSH-insensitive FRT and buffalo rat liver (BRL) cells, which lack functional TSH receptors. SOCS-1 and SOCS-3 are constitutively expressed in FRTL-5 cells, but not in FRT and BRL cells. IFN-gamma up-regulated SOCS-1 and SOCS-3 RNA and protein in FRTL-5 cells, as reported previously for nonthyroid cells. Interestingly, TSH also significantly induced SOCS-1 and SOCS-3 in FRTL-5 cells, but not in FRT and BRL cells. When SOCS-1 or SOCS-3 was overexpressed in FRTL-5 cells, STAT1 phosphorylation at Y701 and STAT1/DNA complex formation in response to IFN-gamma were reduced. Furthermore, overexpression of either SOCS-1 or SOCS-3 significantly inhibited the IFN-gamma-mediated transactivation of the rat ICAM-1 (intercellular adhesion molecule-1) promoter. TSH and IFN-gamma had different effects on STAT1 and STAT3 phosphorylation. The phosphorylation of Y701 in STAT1, which is responsible for homodimer formation, nuclear translocation, and DNA binding, was specifically stimulated by IFN-gamma, but not by TSH or forskolin. However, the phosphorylation of S727 in STAT1 was induced by IFN-gamma, TSH, and forskolin. TSH induced phosphorylation of both Y705 and S727 in STAT3, while IFN-gamma phosphorylated only the Y705. In addition, we found that SOCS-3 was associated with JAK1 and JAK2 and that these associations were stimulated by TSH. These findings demonstrate that TSH induces SOCS in thyroid cells and provides the evidence of signal cross-talk between TSH and cytokines in thyroid cells.

Animals↗

PubMed2000

Involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) in the thyrotropin signaling pathway.

TSH is an important physiological regulator of growth and function in thyroid gland. The mechanism of action of TSH depends on interaction with its receptor coupled to heterotrimeric G proteins. We show here that TSH induces the phosphorylation of tyrosine in the intracellular kinases Janus kinase 1 (JAK1) and -2 (JAK2) in rat thyroid cells and in Chinese hamster ovary (CHO) cells transfected with human TSH receptor (TSHR). The JAK family substrates STAT3 (signal transducers and activators of transcription) are rapidly tyrosine phosphorylated in response to TSH. We also find that JAK1, JAK2, and STAT3 coprecipitate with the TSHR, indicating that the TSHR may be able to signal through the intracellular phosphorylation pathway used by the JAK-STAT cascade. TSH increases STAT3-mediated promoter activity and also induces endogenous SOCS-1 (suppressor of cytokine signaling-1) gene expression, a known target gene of STAT3. The expression of a dominant negative form of STAT3 completely inhibited TSH-mediated SOCS-1 expression. These findings suggest that the TSHR is able to signal through JAK/STAT3 pathways.

Animals↗

PubMed2000

Increased prevalence of autoimmune thyroid disease in patients with type 1 diabetes.

BACKGROUND: Type 1 diabetes mellitus is frequently associated with other autoimmune diseases. The occurrence of common features of autoimmune diseases and the coassociation of multiple autoimmune diseases in the same individual or family supports the notion that there may be common genetic factors. METHODS: To investigate potential clustering of autoimmune thyroid disease (ATD) among type 1 diabetes patients and the contribution of common susceptibility genes to this, HLA DR/DQ alleles as well as antithyroid autoantibodies were measured in 115 Korean patients with type 1 diabetes and their 96 first-degree family members. RESULTS: Twenty-five percent of the patients had ATD, whereas 3 of 36 (8%) age-matched normal controls had ATD (RR = 3.7, p < 0.05). Twenty-six of ninty-six (27%) type 1 diabetes family members had ATD. No differences in the distribution of HLA alleles/haplotypes and genotypes between the patients with and without ATD were found. CONCLUSION: From this finding, we could assess that individuals with type 1 diabetes and their relatives frequently develop ATD, perhaps due to common susceptibility genes that are shared among first degree relatives.

Adult↗

PubMed1999

Different bioactivities of human thyrotropin receptors with different signal peptides.

For investigation of the mechanism and pathogenesis of Graves' disease, availability of a large amount of functional human thyrotropin receptor (TSHR) capable of recognition by Graves' autoantibodies is essential. Many attempts have been made to produce the extracellular domain of TSH receptor (TSHRE) in a baculovirus expression system. However, the receptor is expressed as an insoluble form and the refolded protein is often not recognized by the autoantibodies. In this study, we found that the TSHRE expressed with its own signal peptide (VL3-RE) in insect cells is retained inside of the cells and found in both soluble and insoluble fractions in equal proportion. The signal peptide is not removed. The receptor in the soluble fraction is not recognized by either TSH or Graves' autoantibodies. The TSHRE with an insect-specific mellitin signal peptide (Mel-RE) is also retained inside of the cell and found in both the soluble and insoluble fractions in equal proportion. However, the signal peptide is removed and the receptor is recognized by the Graves' autoantibodies but not by TSH. Also, the amount of Mel-RE expressed was 5-10-fold higher than VL3-RE. The two receptor preparations apparently have the same degree of glycosylation as evidenced by the same increased mass (approximately 15 kDa) due to glycosylation. However, the two receptors have different affinity for an anion-exchange resin and different pI. Deglycosylated receptors have the same pI. This suggests that the composition of sugars may be different. Taken together, the results suggest that the two receptors are modified and folded differently by different pathways due to the presence of different signal peptides. Use of an insect-specific signal peptide is recommended for expression of TSHR that is recognized by Graves' autoantibodies in a baculovirus system.

Autoantibodies↗

PubMed1999

Metabolic effect of decreasing nonesterified fatty acid levels with acipimox in hyperthyroid patients.

Glucose intolerance is often found in patients with hyperthyroidism, but the pathogenetic mechanisms are not fully understood. Since lipolysis is increased in hyperthyroidism, elevated plasma nonesterified fatty acids (NEFAs) may contribute to abnormal glucose metabolism in hyperthyroidism. The aim of this study was to investigate whether decreasing the plasma NEFA level with acipimox can affect glucose metabolism in hyperthyroidism. We performed an intravenous glucose tolerance test (IVGTT) with acipimox 250 mg or placebo in six untreated hyperthyroid men and six age- and body mass index (BMI)-matched controls. Fasting plasma NEFA levels were significantly higher in the hyperthyroid patients versus the controls (997.0 +/- 303.4 v290.5 +/- 169.1 micromol/L, P < .001). Plasma NEFAs decreased rapidly with acipimox treatment in both controls and hyperthyroid patients. In the controls, the glucose disappearance constant (K(G)) was not different for acipimox treatment versus placebo (2.18 +/- 0.62 v 2.42 +/- 1.00% x min(-1)). In hyperthyroid patients, acipimox treatment increased the K(G) significantly compared with placebo treatment (2.44 +/- 0.84 v 1.58 +/- 0.37% x min(-1), P < .05). Changes in K(G) values with acipimox treatment were inversely correlated with changes in plasma NEFA levels (r = -.65, P < .05). Acipimox treatment increased the acute insulin response (AIR) in hyperthyroid patients (943 +/- 381 v 698 +/- 279 microU/mL x min, P < .05), whereas it did not change the AIR in controls. Changes in the AIR with acipimox treatment correlated significantly with changes in the K(G) (r = .70, P < .05). There was a weak correlation between changes in the AIR with acipimox treatment and changes in plasma NEFA levels (r = -.55, P = .06). In summary, decreasing the plasma NEFA level with acipimox in hyperthyroid patients increases both the K(G) and AIR during an IVGTT. These findings suggest that the abnormal glucose metabolism in hyperthyroidism could be attributed, at least in part, to the increase of plasma NEFA.

Administration, Oral↗