Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroid axis.

Abstract

The cytokines interleukin-1 (IL-1) and IL-6 are thought to be important mediators in the suppression of thyroid function during nonthyroidal illness. In this study we compared the effects of IL-1 and IL-6 infusion on the hypothalamus-pituitary-thyroid axis in rats. Cytokines were administered by continuous ip infusion of 4 micrograms IL-1 alpha/day for 1, 2, or 7 days or of 15 micrograms IL-6/day for 7 days. Body weight and temperature, food and water intake, and plasma TSH, T4, free T4 (FT4), T3, and corticosterone levels were measured daily, and hypothalamic pro-TRH messenger RNA (mRNA) and hypophysial TSH beta mRNA were determined after termination of the experiments. Compared with saline-treated controls, infusion of IL-1, but not of IL-6, produced a transient decrease in food and water intake, a transient increase in body temperature, and a prolonged decrease in body weight. Both cytokines caused transient decreases in plasma TSH and T4, which were greater and more prolonged with IL-1 than with IL-6, whereas they effected similar transient increases in the plasma FT4 fraction. Infusion with IL-1, but not IL-6, also induced transient decreases in plasma FT4 and T3 and a transient increase in plasma corticosterone. Hypothalamic pro-TRH mRNA was significantly decreased (-73%) after 7 days, but not after 1 or 2 days, of IL-1 infusion and was unaffected by IL-6 infusion. Hypophysial TSH beta mRNA was significantly decreased after 2 (-62%) and 7 (-62%) days, but not after 1 day, of IL-1 infusion and was unaffected by IL-6 infusion. These results are in agreement with previous findings that IL-1, more so than IL-6, directly inhibits thyroid hormone production. They also indicate that IL-1 and IL-6 both decrease plasma T4 binding. Furthermore, both cytokines induce an acute and dramatic decrease in plasma TSH before (IL-1) or even without (IL-6) a decrease in hypothalamic pro-TRH mRNA or hypophysial TSH beta mRNA, suggesting that the acute decrease in TSH secretion is not caused by decreased pro-TRH and TSH beta gene expression. The TSH-suppressive effect of IL-6, either administered as such or induced by IL-1 infusion, may be due to a direct effect on the thyrotroph, whereas additional effects of IL-1 may involve changes in the hypothalamic release of somatostatin or TRH.(ABSTRACT TRUNCATED AT 400 WORDS)

The molecular basis of the non-thyroidal illness syndrome

“…However, acute injection of cytokines failed to induce NTIS like features, except for interferon gamma (IFNg) which reduces serum T 3 and T 4 (Boelen et al 1995). Chronic infusions with IL1 and IL6 on the other hand mimick certain symptoms such as decreased serum T 4 and T 3 and decreased thyrotropinreleasing hormone (TRH) expression in the hypothalamus in mice (van Haasteren et al 1994), while chronic IL1b infusions mimicks certain aspects of NTIS in the rat (Hermus et al 1992).…”

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines

“…The continuous IL-6 intraperitoneal infusion (15 mg/day for 7 consecutive days) in rats was associated with a transient decrease in serum T4 and TSH, although less than that caused by IL-1 [145]. In latter study, pro-TRH mRNA hypothalamic and pituitary TSH-b mRNA were unaffected by IL-6, suggesting that the effects of IL-6 on TSH might not necessarily be associated with a decreased synthesis of thyrotropin [145]. On the other hand, the observation that the intracerebroventricular IL-6 administration to rats was followed by a decrease in serum TSH and an increase in serum adrenocorticotropin (ACTH) concentrations, while these changes could be reproduced in hemipituitaries only for ACTH, but not for TSH, suggested that the action of IL-6 on TSH might be exerted predominantly at the hypothalamic levels [146].…”

“…Changes in serum thyroid hormone concentrations could effectively be ascribed to IL-6, since they could be prevented by IL-6 preincubation with its neutralizing antibody [144]. The continuous IL-6 intraperitoneal infusion (15 mg/day for 7 consecutive days) in rats was associated with a transient decrease in serum T4 and TSH, although less than that caused by IL-1 [145]. In latter study, pro-TRH mRNA hypothalamic and pituitary TSH-b mRNA were unaffected by IL-6, suggesting that the effects of IL-6 on TSH might not necessarily be associated with a decreased synthesis of thyrotropin [145].…”

“…The increase in IL-6 plasmatic could stimulate the hepatic synthesis of triacylglycerol, contributing to hypertriglyceridemia associated with visceral obesity. Data on relationship of thyroid hormones and IL-6 in obesity are scarce, but the association between reduction of T3 circulating levels and increasing pro-inflammatory cytokines, particularly IL-6, is described in the literature in both animals' models and human studies -septic patients and in patients with systemic inflammatory response [144,145]. The acute subcutaneous administration of IL-6 (5 mg) in rats was associated with decrease in T4,T3 and TSH serum concentrations, while the T4/T3 ratio decreased, suggesting that T4 deiodination was not affected [144].…”

Tiroidektomize Ratlarda Serum IL-1β, IL-6, IL-10 ve TNF-α Seviyeleri

“…Furthermore, now it is well known that IL-1, IL-6 and TNF-α could play central role in the pathogenesis of non thyroidal illness (NTI) syndrome by acting on hypothalamus pituitary-thyroid axis [13] . IL-1, IL-6 and TNF-α are effect as suppressor mediators on thyroid hormones during NTI [14] . Also, Bartalena et al [15] tested that hypothesis in rats with induced hypothyroidism by administration of the methimazole throughout 3 weeks and they concluded that 48 hours after a single dose recombinant human IL-6 injection could reduce serum T3, T4 and TSH concentrations due to central effects of the cytokine.…”