The first characterised mammalian Toll-like receptor (TLR) was described in 1997, i.e. TLR4, which can detect lipopolysaccharide (LPS) from Gram-negative bacteria. Since then several proteins structurally related to TLR4 were identified (TLR1-10). For example, TLR2 can bind to lipopeptides from Gram-positive bacteria. For both receptors human polymorphisms have been identified (TLR4 up to 14% and TLR2 up to 10% in Europe) and linked to several clinical conditions such as asthma, coronary artery stenosis, myocardial infarction, peridontitis, renal transplantation, stroke or ulcerative colitis as well as burn trauma and S. aureus infection just to name a few. Numbers of patients enrolled in these polymorphism studies vary between 20 and 2000. At present, these studies demonstrate controversial results in terms of outcome. This might be explained by the fact that only small patient numbers have been used as well as that some of these trials did not study patient outcome as an endpoint. Recent data from our lab demonstrate a novel link between the innate immune system and the endocrine stress response mediated by TLRs. TLR2 and TLR4 are expressed in human and mice adrenals and TLR2 deficiency is associated with an impaired glucocorticoid response. We present here pre-clinical data and results of a trial (Toll Police S1=Toll-like receptor Polymorphism in cardiovascular elective Surgery Trial 1) conducted in 450 patients undergoing elective cardiac surgery. TLR2 and TLR4 polymorphisms were determined and correlated with 28 days mortality (among other factors) following surgery. The lecture will present pre-clinical results and design, population and outcome data from the trial. Furthermore, we will highlight limitations and drawbacks as well as suggestions for future trials.
Bornstein et al. Horm Metab Res 2004; Bornstein et al. PNAS 2004; Zacharowski et al. PNAS 2006; Tran et al. J Clin Endo Metab 2007; Kanczkowski et al. Horm Metab Res 2007.
03 - 07 May 2008
European Society of Endocrinology