In a series of septic patients studied shortly after admission to an ICU, total T4, free T4, total T3, and TSH were depressed, and IL-1b, sIL-2R, IL-6, and TNFa were elevated(88). The data suggest central suppression of TSH as the cause of the problem, but the relation to cytokines is unclear, as seen in  the following reports. The hypothalamo-pituitary-adrenal axis was activated as expected. Hermus et al. ( 89) showed that continuous infusion of IL-1 in rats cause suppression of TSH, T3, and free T4. Higher doses of IL-1 were accompanied by a febrile reaction and suppression of food intake, which presumably played some role in the altered thyroid hormone economy. IL-1 did not reproduce the diminution in hepatic 5'-deiodinase activity believed to be so characteristic of NTIS. IL-1 is also known to impair thyroid hormone synthesis by human thyrocytes, and is enhanced in many diseases associated with NTIS ( 90). Van der Poll et al. ( 91) studied the effect of IL-1 receptor blockade in human volunteers, to determine if it could alter the NTIS induced by endotoxin. Blockade of IL-1 activity was achieved by infusing recombinant human IL-1 receptor antagonist, but this did not prevent the drop in T4, free T4, T3, and TSH, or rise in reverse T3 caused by endotoxin. This is evidence against an important role for IL-1.

Interferon-g (100 mg/m2 ) administered subcutaneously to normal volunteers did not alter TNFa levels, caused a small elevation of IL-6 levels, and thus do not support a role for Interferon-g in the pathogenesis of the euthyroid sick syndrome in humans (92).

TNF is another pro-inflammatory cytokine that is thought to be involved in many of the illnesses associated with NTIS. Infusion of recombinant TNF in man, by Vanderpool et al., produced a decrease in serum T3 and TSH, and increase in rT3. Free T4 was transiently elevated in association with a significant rise in FFA levels. These studies suggest that TNF could be involved when recombinant IL-6, given to humans, activates the hypothalamic pituitary axis and, as noted above, this could secondarily suppress TSH production. However, Chopra et al. ( 93) did not find TNF to be closely correlated with hormone changes in NTIS.  Van der Poll et al (94,95) gave human subjects endotoxin, which caused lowering of T4, free T4, T3 and TSH. TNF blockade by a recombinant TNF receptor-IgG fusion protein did not alter the response, indicating that TNF did not cause the changes in hormone economy induced by administration of endotoxin. Nagaya et al (96) have proposed a mechanism through which TNF could reduce serum T3. TNF alpha was found during in vitro studies to activate NFkappa B, which in turn inhibits the T3 induced expression of 5’- DI, which would lower T3 generation in liver.

Serum IL-6 is often elevated in NTIS ( 97), and its level is inversely related to T3 levels (9 8). Stouthard et al. (9 9) gave recombinant human IL-6 chronically to human volunteers. Short term infusion of IL-6 caused a suppression of TSH, but daily injections over 42 days cause only a modest decrease in T3, and a transient increase in reverse T3, and in free T4 concentrations (Fig.6). IL-6 could be involved in the NTIS syndrome, although the mechanism was not defined. In an animal model of NTIS studied by Wiersinga and collaborators (10 0), antibody blockade of IL-6 failed to prevent the induced changes in thyroid hormone economy typical of NTIS. Boelen et al. studied the levels of IFN , IL-8, and IL-10 in patients with NTIS and found no evidence that they had a pathogenic role (101). Short term administration of recombinant IFN-gamma to normal subjects caused a minimal elevation of Il-6, no alteration in TNF, and did not significantly alter thyroid hormone levels( 102). Michalaki et al observed that serum T3 drops early after abdominal surgery as an early manifestation of the NTIS syndrome, prior to an increase in serum IL-6 or TNFa, suggesting that these changes in cytokines do not induce the drop in T3 (103).

The potential interaction between cytokines and the hypothalamic pituitary thyroid axis is certainly complicated, and cytokines themselves operate in a network. For example, IL-1 and TNF can stimulate secretion of IL-6. Activation of TNF and IL-1 production is associated with the occurrence of cytokine inhibitors in serum, which are actually fragments of the cytokine receptor, or actual receptor antagonists. "Soluble TNF receptor" and "IL-1 RA" are receptor antagonists, which can inhibit the function of the free cytokines. These molecules are increased in many infectious, inflammatory, and neoplastic conditions. Boelen et al. ( 104) found evidence that the NTIS is "an acute phase response" generated by activation of a cytokine network. Soluble TNF , soluble TNF receptor, soluble IL-2 receptor antagonist, and IL-6 all inversely correlated with serum T3 levels. At least we can be convinced that these cytokine changes co-occur with changes in T3 and probably play a pathogenic role by mechanisms yet unknown.