Tumor Necrosis Factor-α is Inversely Related to Free Thyroxine in Euthyroid Subjects Without Diabetes

Abstract

Lower thyroid functional status within the euthyroid range may confer increased atherosclerosis susceptibility, as evidenced by increased intima media thickness and coronary artery calcification. Associations of lower thyroid functional status with pro-atherogenic (inflammatory) biomarkers may also extend into the euthyroid range. Here we established relationships of plasma tumor necrosis factor-α (TNF-α) with thyroid stimulating hormone (TSH) and free thyroxine (free T) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM). Fasting TSH, free T, and TNF-α were measured in 81 nondiabetic subjects and in 73 T2DM subjects with Type 2 diabetes mellitus (T2DM; insulin using subjects were excluded) with TSH and free T levels each within the institutional reference ranges. TSH was similar and free T was slightly higher in T2DM (p<0.016). Plasma TNF-α was increased in T2DM (p=0.007). In nondiabetic subjects, TNF-α was correlated inversely with free T (r=-0.25, p=0.022), whereas such a relationship was absent in T2DM subjects (r=0.058, p=0.63). Multivariable linear regression analysis showed that in nondiabetic subjects TNF-α remained inversely associated with free T after adjustment for age and sex (β=-0.243, p=0.032) and additionally for thyroid autoantibodies (β=-0.251, p=0.027), contrasting the lack of relationship in T2DM subjects (interaction: p=0.053). In T2DM subjects, TNF-α was also unrelated to free T taking account of possible confounders, as well as after exclusion of subjects using metformin or antihypertensive medication. In conclusion, higher levels of TNF-α relate to lower free T. Low-normal thyroid function could influence pro-inflammatory pathways. This relationship appears to be disturbed in T2DM.

Serum paraoxonase‐1 activity is inversely related to free thyroxine in euthyroid subjects: The PREVEND Cohort Study

“…12,13 Moreover, increased levels of oxidized LDL have been demonstrated in euthyroid subjects with high normal TSH levels. 14 Taken together, these data 14,[45][46][47] make it unlikely that a higher PON-1 activity in relation to low-normal thyroid function is explained by thyroid hormone-mediated effects on IL-1 and TNF-a or on (systemic) oxidative stress.…”

“…45 Hypothyroidism may increase IL-1 and TNF-a, 46 whereas higher levels of TNF-a are also found in subjects with low-normal thyroid function. 47 In addition, oxidized lipids are recognized to inhibit PON-1 activity. 12,48,49 In this context, it is relevant that low-density lipoprotein (LDL) oxidation in vitro is exaggerated in both hypothyroidism and hyperthyroidism.…”

“…Paraoxonase‐1 (PON‐1) is downregulated by interleukin‐1 (IL‐1) and tumour necrosis factor‐α (TNF‐α) . Hypothyroidism may increase IL‐1 and TNF‐α, whereas higher levels of TNF‐α are also found in subjects with low‐normal thyroid function . In addition, oxidized lipids are recognized to inhibit PON‐1 activity .…”

Association Between Sensitivity to Thyroid Hormones and Metabolic Dysfunction-Associated Fatty Liver Disease in Euthyroid Subjects: A Cross-Sectional Study

“…33 The underlying mechanisms of relationships between sensitivity indices to THs and MAFLD stay entirely unknown, but may contain chronic inflammation, dysregulation of mitochondrial homeostasis, endoplasmic reticulum stress and decreased insulin sensitivity. [34][35][36][37][38] Chronic inflammation was considered to be one of the key pathogenesis of MAFLD and could promote the incidence of MAFLD. 35 Studies revealed that low FT4 was related to higher levels of inflammatory biomarkers (eg, tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6 and interferon-γ).…”

Screening for New Markers to Assess Thyroid Hormone Action by OMICs Analysis of Human Samples

“…Moreover, the detected upregulation of the lipopolysaccharide binding protein (LBP), an acute-phase protein, and the corresponding receptor indicated an involvement in immunological responses. The complex and bidirectional relationship between THs and processes of the immune response is subject of an ongoing discussion [58][59][60]. LBP binds to lipopolysaccharides of bacteria and interacts with the CD14 receptor that triggers an immune response, leading to M1activation of macrophages and consequently an increased production of proinflammatory cytokines like tumor necrosis factor alpha (TNFα).…”