Sharon Alex

Suppression of thyrotropin-releasing hormone gene expression by interleukin-1-beta in the rat : implications for nonthyroidal illness

Nonthyroidal illness is characterized by low thyroid hormone levels and inappropriately normal or decreased TSH levels. To determine whether the hypothalamus contributes to these responses, TRH gene expression in hypophysiotropic neurons of the paraventricular nucleus (PVN) was investigated using semiquantitative in situ hybridization histochemistry in an animal model of nonthyroidal illness. Following the systemic administration of bacterial lipopolysaccharide (LPS; 250 micrograms/100 g BW), plasma T4, T3 and TSH were reduced but this was not associated with an increase in the content of proTRH mRNA in the PVN as occurs when plasma T4 and T3 concentrations fall during primary hypothyroidism. Constant infusion of human interleukin-1 beta (IL-1 beta) into the cerebrospinal fluid also reduced plasma T4 concentration. This persisted for the duration of the infusion but TSH was only suppressed after 7 days of infusion when body weight had declined. By 24 h, the content of proTRH mRNA in the PVN in IL-1 beta infused animals was significantly reduced from control values. These studies indicate that the peripheral administration of endotoxin or central administration of IL-1 beta in the rat is associated with a proTRH mRNA content in the PVN that may be inappropriately normal or reduced for the level of circulating thyroid hormone. We propose that the inability of hypophysiotropic neurons to induce TRH gene expression in nonthyroidal illness, when circulating thyroid hormone levels are low, is one of several factors that contributes to the inability of the anterior pituitary to increase its secretion of TSH.

Iodine Content of Rat Thyroglobulin Affects its Antigenicity in Inducing Lymphocytic Thyroiditis in the BB/Wor Rat

The BB/Wor rat develops spontaneous insulin dependent diabetes mellitus (DM) and lymphocytic thyroiditis (LT). We have recently demonstrated that immunization of BB/Wor rats with allogeneic thyroglobulin (Tg) induces LT at an early age. The incidence of spontaneous and Tg induced LT is extremely variable among different BB/Wor sublines. It has been shown that high iodine diet significantly increases the incidence of spontaneous lymphocytic thyroiditis (LT) and low iodine diet significantly decreases the incidence of LT in genetically predisposed BB/Wor rats. Recent studies on thyroglobulin (Tg) induced LT in chicken and mouse have shown that iodine rich Tg is far more antigenic than Tg with a low iodine content, suggesting that a high iodine diet increases the immunogenicity of Tg molecule. In order to determine whether the extent of Tg iodination would affect its immunogenicity in the BB/Wor rats, the current study was carried out. Normal iodine Tg (NTg) or low iodine Tg (LTg) was obtained from thyroids of rats that were placed on regular diet or regular diet plus 0.5% methimazole, respectively. 120 rats from the NB (highly susceptible) and BB (low susceptible) sublines were randomized in three groups. Immunization was carried out with a 1:1 emulsion of complete Freunds adjuvant (CFA) and LTg, NTg (0.6 mg/rat) or saline at 30 and 37 days of age. Since spontaneous LT rarely occurs before age 75 days, rats were sacrificed at age 65 days to specifically study Tg induced LT. Immunization with NTg induced LT in 31% of the NB rats, but not in the BB subline. LTg did not induce LT in either subline.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental regulation of thyrotropin receptor gene expression in the fetal and neonatal rat thyroid: relation to thyroid morphology and to thyroid-specific gene expression.

The TSH receptor plays a pivotal role in thyroid gland function, growth, and differentiation, but little is known about its role or regulation in the fetus and neonate. To explore these questions, we systematically evaluated TSH receptor gene expression at the level of messenger RNA (mRNA) in thyroid glands obtained from rat fetuses and neonates, from 14 days gestation to day 5 of postnatal life. Results were compared with histological evidence of differentiation and to thyroid-specific gene expression. Northern blot and RT-PCR analysis revealed that TSH mRNA was first detected at low levels on fetal day 15, but it increased 3- to 15-fold on fetal days 17–18. Up-regulation of TSH receptor mRNA on fetal day 17–18 was accompanied by the first appearance of colloid formation and of follicular development on morphological examination. It was also paralleled by increased expression of the thyroid-specific genes thyroglobulin (Tg) and thyroid peroxidase. Unexpectedly, TSH mRNA abundance was 2- to 3-fold higher ...

The inhibitory effect of large doses of methimazole on iodine induced lymphocytic thyroiditis and serum anti-thyroglobulin antibody titers in BB/Wor rats.

The BB/Wor rat spontaneously develops autoimmune insulin dependent diabetes mellitus and lymphocytic thyroiditis (LT). Excess iodine ingestion enhances and low iodine diet decreases the incidence of LT in this rat model but does not affect the incidence of diabetes mellitus. The administration of a low dose of methimazole (MMI; 870 ng/gm bw ip daily) from 30–90 days of age had no significant effect on thyroid function or on the incidence of iodine induced LT and serum anti-thyroglobulin (Tg) antibodies measured by an ELISA assay. A large dose of MMI (0.05% in the drinking water) induced goiter and hypothyroidism. In addition, the incidence of LT was markedly attenuated (76% vs 6%, p < 0.001) and reduced titers of serum anti-Tg antibodies (0.59 ± 0.1 OD vs 0.08 ± 0.01, p < 0.001) were observed. This inhibitory effect of MMI on the occurrence of iodine induced LT in the BB/Wor rat may be due to the lower antigenicity of the poorly iodinated Tg secondary to MMI therapy and/or to an immunosuppressant effect of MMI itself.

Thyroglobulin Induced Lymphocytic Thyroiditis in two Sublines of BB/WOR Rats

The BB/Wor rat develops spontaneous insulin dependent diabetes mellitus (DM) and lymphocytic thyroiditis (LT). We have recently demonstrated that although the incidence of spontaneous DM is relatively constant among different inbred BB/Wor sublines the incidence of LT is extremely variable. Experimental LT can be induced in some animal species by immunization with thyroglobulin (Tg). The differences in susceptibility of Tg induced LT between a high incidence LT subline (NB) and a low incidence subline (BB) were determined after immunization with Tg obtained from Wistar rat thyroids. Immunization was accomplished using 0.6 mg Tg in complete Freunds adjuvant (FA) or FA alone at 30 and 37 days. Since spontaneous LT rarely occurs before age 75 days, rats were sacrificed at age 65 days to specifically study Tg induced LT. Immunization with Tg induced LT in the NB subline but not in the BB subline. Anti-Tg antibody (Ab) titers, T4-Ab and T3-Ab were all increased in both Tg immunized sublines but were significantly higher in Tg immunized NB rats than in Tg immunized BB rats. The increase in T4-Ab or T3-Ab resulted in factitiously low serum T4 and T3 values when a single Ab technique with polyethylene glycol (PEG) precipitation was used in the RIA. There was a dissociation in the incidence of Tg induced LT and Ab production. Although Tg immunization failed to induce LT in the BB subline, anti-Tg Ab were significantly elevated as well as both T4-Ab and T3-Ab, suggesting that anti-Tg Ab titers per se are not tightly correlated with the occurrence of LT.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ciamexone on lymphocytic thyroiditis and insulin-dependent diabetes mellitus in the BB/Wor rat

Previous studies have suggested that ciamexone, a 2-cyan-aziridine derivative, is a selective immunomodulatory agent with potential therapeutic application in a variety of autoimmune diseases. In the present study, the effects of ciamexone on autoimmune lymphocytic thyroiditis and diabetes mellitus were studied in the BB rat. The data suggest that, in this animal model, ciamexone does not affect the frequency of autoimmune diabetes or lymphocytic thyroiditis nor does it affect the serum TSH or T4 concentrations.

NORMAL SERUM T3 POSTNATAL SURGE AND INCREASED REVERSE T3 LEVELS IN SELENIUM-DEFICIENT RAT PUPS

In adult rats, selenium (Se) deficiency markedly decreases liver type I outer-ring 5′ deiodinase (5′D-I, a selenoenzyme convening T4 into T3), resulting in a 40% increase in serum T4 concentrations. Serum T3 and reverse T3 (rT3) concentrations are unchanged or marginally decreased or increased, respectively. In rat fetuses, serum T4 and rT3 concentrations are not affected by selenium deficiency. We studied the effect of Se deficiency on thyroid function in the rat neonate. 28 weanling female rats were fed a Se replete (Se+) or Se deficient (Se−) diet for 4 wk prior to mating and throughout gestation. 2-3 pups from each litter were sacrificed 7, 14 and 21 days after delivery. Serum T4, T3, rT3 and TSH concentrations and liver 5′D-I activity, to assess Se deficiency, were measured.*P<0.001 compared to corresponding Se+group Mean(SE).In Se- pups, the decrease in 5′D-I activity was >89% confirming Se deficiency (P<0.001). In contrast to adult rats, Se deficiency causes no increase in serum T4 in 1 and 2 wk old pups and only a 20% increase in 3 wk old pups, but results in a 60-250% increase in serum rT3.Conclusion: 1) In the rat neonate, the 500 to 600% surge in serum T3 levels observed physiologically after birth is independent of liver 5′D-I activity, strongly suggesting that T4 to T3 conversion by peripheral tissues is not a major source of T3 in the neonate; 2) In contrast, serum rT3 levels increase markedly in Se- pups as early as the 7th postnatal day, suggesting that liver 5′D-I is important in rT3 metabolism.