Genetic variation of TLR4 influences immunoendocrine stress response: an observational study in cardiac surgical patients

Alexander Koch,Matthias Schott,Kai Zacharowski,Dirk Grotemeyer,Stefan R Bornstein,Lutz Hamann,Ralf R Schumann,Olaf Boehm,Muhammed Kurt,Carsten Schwenke

doi:10.1186/cc10130

Abstract

IntroductionSystemic inflammation (for example, following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum.MethodsA total of 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and granulocyte macrophage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day.ResultsThirteen patients were identified as TLR2 SNP carriers, 51 as TLR4 SNP carriers and 274 patients as non-carriers. Basal levels of ACTH, cortisol and cytokines did not differ among groups. In all three groups a significant, transient perioperative rise of cortisol could be observed. However, only in the non-carrier group this was accompanied by a significant ACTH rise. TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers (mean (95% confidence intervals)) non-carriers: 201.9 (187.7 to 216.1) pg/ml; TLR4 SNP carriers: 149.9 (118.4 to 181.5) pg/ml; TLR2 SNP carriers: 176.4 ((110.5 to 242.3) pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks (mean (95% confidence intervals)): IL-8: non-carriers: 42.6 (36.7 to 48.5) pg/ml, TLR4 SNP carriers: 23.7 (10.7 to 36.8) pg/ml; IL-10: non-carriers: 83.8 (70.3 to 97.4) pg/ml, TLR4 SNP carriers: 54.2 (24.1 to 84.2) pg/ml; GM-CSF: non-carriers: 33.0 (27.8 to 38.3) pg/ml, TLR4 SNP carriers: 20.2 (8.6 to 31.8) pg/ml). No significant changes over time or between the groups were found for the other cytokines.ConclusionsRegulation of the immunoendocrine stress response during systemic inflammation is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this genotype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (for example, adrenal insufficiency) during systemic inflammation and sepsis.

Highlights

Systemic inflammation involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response
To reduce the undue influence of subjects demonstrating undetected HPA axis pathologies, preoperative systemic inflammation or measurement related discrepancies, outliers were defined as values above 99.5% tolerance intervals (TI) and subjects demonstrating these outliers were excluded from analyzes
A total of 338 patients, all European Caucasians were included; 13 patients were identified as TLR2, 51 as TLR4 single nucleotide polymorphisms (SNP) carriers, 274 patients were identified as non-carriers

Summary

Introduction

Systemic inflammation (for example, following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. In TLR2 deficient mice, adrenal glands are significantly larger compared to wild-type mice. Inducing a systemic inflammation with bacterial wall components in TLR2 deficient mice leads to an impaired release of both corticosterone and pro-inflammatory cytokines compared to wild-type animals [6]. A similar difference of physiology and pathophysiology of the HPA axis exists between wild-type and TLR4 deficient mice. Under physiological conditions the cortex of the adrenal glands is significantly enlarged and plasma concentrations of corticosterone and the pro-inflammatory cytokines tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-12 are significantly higher when compared to wild-type animals. Systemic inflammation induces an increase of corticosterone plasma concentration in wildtype, but a decrease in TLR4 deficient mice [7]

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