During critical illness, major changes in serum thyroid hormone metabolism without primary involvement of the thyroid gland can occur. (Wartofsky and Burman ¹⁹⁸²; Chopra et al. ¹⁹⁸³) This altered thyroid metabolism, referred to as non-thyroidal illness syndrome, is characterized by low serum levels of triiodothyronine and thyroxine, without changes in thyrotropin levels. Although the pathogenesis of non-thyroidal illness syndrome remains poorly understood, the reduction of peripheral thyroid levels is most probably under the influence of pro-inflammatory cytokines, and interleukin-6 in particular. (Davies et al. ¹⁹⁹⁶; Boelen et al. ¹⁹⁹⁶; Papanicolaou ²⁰⁰⁰)

Conversely, it has been suggested that thyroid hormones induce production of inflammatory cytokines. Earlier studies have demonstrated higher circulating levels of pro-inflammatory cytokines in patients with hyperthyroidism. (Lakatos et al. ¹⁹⁹⁷; Siddiqi et al. ¹⁹⁹⁸) These elevated cytokine levels were independent of autoimmune inflammation usually associated with thyroid disease. Moreover, treatment of hyperthyroidism was associated with lowering of serum pro-inflammatory cytokine levels. (Siddiqi et al. ¹⁹⁹⁹)

In view of these considerations, we postulated a mutual association between triiodothyronine and pro-inflammatory cytokines, in which serum free triiodothyronine has a stimulatory effect on the pro-inflammatory cytokine production capacity, whilst pro-inflammatory cytokines in turn temper this stimulatory effect of triiodothyronine by lowering peripheral thyroid hormone levels. To test this hypothesis, we first assessed the relation between various circulating inflammatory markers and serum thyroid function parameters in the Leiden 85-plus Study, a prospective population-based study among the oldest old. Next, we assessed the relation between serum thyroid function parameters and ex vivo cytokine production capacity. Physical illness was considered a potential confounder in the relation between serum thyroid function parameters and cytokine production capacity.

The baseline characteristics of the 496 participants in the study are presented in Table 1. All study participants were 85 years of age and 327 of 496 participants (65.9%) were female.

Table 2 shows the association between various serum inflammatory markers and different thyroid parameters. Neither CRP nor interleukin-6 were associated with serum thyrotropin or free thyroxine levels. Higher levels of circulating C-reactive protein were significantly related to lower serum levels of free triiodothyronine (p = 0.001). Likewise, higher levels of interleukin-6 were associated with lower levels of triiodothyronine (p = 0.020). We repeated the analyses after excluding persons who on the basis of their CRP levels (higher than 10.0 mg/dL) may be experiencing an acute infection (n = 75). Although after exclusion of subjects with CRP levels above 10 mg/dL the associations between free triiodothyronine levels and CRP and between free triiodothyronine levels and IL-6 lost statistical significance, the effect sizes remained roughly similar, indicating that the observed associations are not completely driven by those with exceptionally high-sensitivity CRP (hsCRP).

Next, we assessed the association between different thyroid function parameters and whole-blood LPS-stimulated cytokine production capacity. The outcomes are given in Table 3. Serum thyrotropin levels and serum free thyroxine levels were not associated with cytokine production capacity. However, higher levels of serum free triiodothyronine concentrations were consistently associated with a higher production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) after whole-blood stimulation with LPS. The relation between triiodothyronine levels and the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) is also illustrated in Fig. 1.

We considered physical illness as a potential confounder of the relation between triiodothyronine levels and cytokine production capacity. Therefore we repeated the analyses after inclusion of parameters of physical disability: ADLs score, IADLs score, MMSE and serum CRP. As apparent from Table 4, correction for these parameters did not substantially affect our results. Also, exclusion of subjects with hsCRP levels higher than 10.0 mg/L (n = 75) from the analyses did not materially affect the observed associations between thyroid function parameters and whole-blood LPS-stimulated cytokine production (data not shown): lower free triiodothyronine levels were associated with lower production capacity of pro-inflammatory cytokines after stimulation with LPS (all p values <0.006). No relation was observed between levels of serum thyrotropin and serum free thyroxine and cytokine production capacity.

The purpose of this study was to investigate a mutual association between triiodothyronine and pro-inflammatory cytokines. Here, we show that higher circulating levels of inflammatory markers were associated with lower levels of free serum triiodothyronine. In turn, lower free triiodothyronine levels were related to lower production capacity of pro-inflammatory cytokines after stimulation with LPS. We did not observe such a relation for levels of serum thyrotropin and serum free thyroxine. Our findings were independent of measures of physical and cognitive impairment.

The observed association between higher unstimulated interleukin-6 levels and lower free serum triiodothyronine in our study agrees with earlier reports which show an association between increased inflammatory cytokines and low triiodothyronine syndrome (Davies et al. ¹⁹⁹⁶; Boelen et al. ¹⁹⁹⁶). Moreover, other studies have demonstrated higher circulating levels of pro-inflammatory cytokines in patients with hyperthyroidism, suggesting a stimulatory effect of thyroid hormones on inflammatory cytokine production. (Siddiqi et al. ¹⁹⁹⁹) However, to our knowledge, this is the first study to address a direct relation between serum thyroid hormone levels and inflammatory cytokine production capacity in blood cells.

Our findings support the hypothesis of a mutual association between triiodothyronine and pro-inflammatory cytokines. As depicted schematically in Fig. 2, in this proposed feedback system, serum free triiodothyronine stimulates the pro-inflammatory cytokine production capacity, while pro-inflammatory cytokines in turn blunt the stimulatory effect of triiodothyronine by lowering peripheral thyroid hormone levels. Lowering of peripheral triiodothyronine levels under the influence of cytokines possibly occurs through regulation of peripheral deiodinase activity, although this putative mechanism has been disputed. The stimulatory effect of triiodothyronine on the cytokine production capacity is likely mediated via nuclear receptors regulating genes involved in the cell-mediated immune response. In humans, high affinity nuclear thyroid hormone receptors have been identified in mononuclear cells (Buergi and Larsen ¹⁹⁸²; Burman et al. ¹⁹⁸⁰). Although these observations provide a tentative explanation for the mutual association between thyroid hormones and cytokines, the epidemiological nature of our study does not allow us to identify the exact underlying mechanisms.

Another possible limitation of our investigation is the advanced age of our study population. We have however no reason to assume that our findings do not apply to younger age categories. Moreover, the fact that the prevalence of thyroid disorders increases with age (Mariotti et al. ¹⁹⁹⁵) makes our observations done in a population of the oldest old all the more clinically relevant. The age-related increase in the prevalence of thyroid disorders might be involved in changes in immune function with age. Maintenance of normal thyroid function could therefore contribute to a preserved immune response in elderly human populations.

Our study has several strong points, particularly the large size of the study population and the variety of studied inflammatory markers, comprising both pro-inflammatory markers as well as anti-inflammatory markers. In addition, our study is unique in that we were able to combine both in vivo en ex vivo information on our study population. Finally, the current study has been done in the general population composed of healthy to moderately healthy subjects, in contrast to most previous studies on the relation between thyroid hormones and immune response which have been done in clinical settings.

In summary, by combining in vivo and ex vivo data, we are the first to demonstrate a potential feedback mechanism between thyroid function and immune production capacity. These observations suggest that maintenance of normal thyroid function contributes to a preserved immune response in elderly human populations. Therefore our findings could have important implications in the care for a growing elderly population.

The Leiden 85-plus Study was in part supported by an unrestricted grant from the Dutch Ministry of Health, Welfare and Sports. This current study was funded by the Netherlands Genomics Initiative/Netherlands Organization for scientific research (NGI/NWO; 05040202 and 050-060-810. NCHA) and the EU funded Network of Excellence Lifespan (FP6 036894). We thank Margo van Schie-Troost and Marja Kersbergen-van Oostrom for their work on the cytokine assays.

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