We investigated the effects of i.v. and intracerebroventricular (i.c.v) administration of increasing doses of recombinant human IL-1 beta, TNF alpha and IL-6 on plasma corticosterone (B) levels in rats. Rats were equipped with a jugular cannula for repeated blood sampling anda subgroup of rats also received an i.c.v implanted cannula. I.v. administration of IL-1 beta, TNF alpha or IL-6 and i.c.v administration of IL-1 beta and IL-6 induced a significant dose-dependent increase in plasma B levels, whereas i.c.v injection of TNF alpha in doses up to 1000 ng/rat was not effective. I.v. pretreatment of rats with anti-CRH antiserum had no significant overall effect on the plasma B response to i.v. administered IL-1 beta (500 and 3000 ng/rat), whereas the plasma B response to i.v. TNF alpha or IL-6 administration (3000 ng/rat) were significantly reduced. I.v. pretreatment of the animals with recombinant human IL-1 receptor antagonist (IL-1ra) significantly blocked the plasma B response to i.v. treatment with IL-1 beta, whereas the TNF alpha- and IL-6-induced increases in plasma B levels were not affected. Our data show that 1) i.v. administration of IL-beta, TNF alpha or IL-6 and i.c.v administration of IL-1 beta or IL-6 dose-dependently stimulate the HPA axis; 2) when given i.v. or i.c.v, IL-1 beta is more powerful than TNF alpha and IL-6 in activating the HPA axis; 3) endogenous CRH is involved in the activation of the HPA axis by acute i.v. administration of TNF alpha and IL-6. It is most likely that in case of i.v. treatment with IL-1 beta a CRH-independent mechanism is involved. This study provides no arguments for the involvement of endogenous IL-1 in TNF alpha- or IL-6-induced activation of the HPA axis.

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)

Experimental procedures. To diminish the stress by the experimental procedures, the animals were handled daily by the experimentator, starting 1 wk before cannulation. Blood was collected from freely moving rats by means of a chronic cannula. Rats were cannulated according to the method described by Steffens (26), with some minor modifications, as described earlier (29). Briefly, under Hypnorm (0.5 ml/kg body wt im; 10 mg/ml fluanisone and 0.315 mg/ml phentanyl citrate; Janssen Pharmaceutica, Tilburg, The Netherlands)-Dormicum (1.0 ml/kg body wt ip; 5.0 mg/ml midazolam hydrochloride; Hoffmann-La Roche, Mijdrecht, The Netherlands)-atropine (0.025 mg/rat sc; Pharmachemie, Haarlem, The Netherlands) anesthesia, a Silastic cannula (ID 0.5 mm; OD 0.94 mm; Dow Corning, Midland, MI) was inserted into the right external jugular vein and passed down to the atrium. The distal end of the cannula was tunneled subcutaneously and exteriorized through a stab wound on the skin of the head, where it was connected to a hooked stainless steel tube. This assembly was anchored to the skull with three stainless steel screws and acrylic cement. During cannulation, rats were continuously exposed to a gas flow of O2-N2O (each 500 ml/min). To keep the cannula patent, it was filled with a 0.9% NaCl solution containing heparin (500 IU/ml; Organon Teknika, Boxtel, The Netherlands) and polyvinylpyrrolidone (1 g/ml; Merck, Darmstadt, Germany).Seven or eight days after cannulation, rats were equipped with intraperitoneally implanted osmotic minipumps (1 (xl/h for 3 days, model 1003D; Alzet, Palo Alto, CA), which were loaded with either sterile pyrogen-free physiological saline or saline containing IL-1, TNF, or IL-1 in combination with TNF. After loading, the pumps were equilibrated and immersed in saline at 37°C for 3-4 h according to the instructions of the manufacturer. The pumps were implanted intraperitoneally under halothane (ICI Pharmaceuticals, Macclesfield, UKJ-CV N20 anesthesia between 1430 and 1630. The indwelling cannula and the osmotic minipumps were tolerated well by the animals, with no signs of discomfort or infection.Protocol. A total of eight groups of rats was continuously infused with saline, IL-1, TNF, or with a combination of IL-1 and TNF. One group of rats was infused with 2.0 (xg IL-1/day

No abstract

No abstract