DAMPs are thought to be involved in this process and previous studies have associated this phenomenon to the innate immune system [32]. In this non-infectious group, we were not able to show a difference Axitinib Sigma in the cytokine response between the genotype groups. This could be in part explained by the hypothesis that the involvement of endogenous danger signals compared with bacterial ligands involves further elements of the innate immune system, or that TLR4 is not a main receptor of DAMPs in this group of patients. This could potentially explain the difference observed in cytokine concentrations between patients following cardiac procedures as compared with the patient group with pneumonia.TIRAP/Mal is an important adaptor molecule for intracellular signaling of both TLR4 and TLR2 [10].

As one of four adaptors for TLR4 signaling [33], TIRAP/Mal functions as a ‘bridging molecule’ for MyD88 [34]. A recently published study postulated a protective effect of the heterozygous TIRAP/Mal variant (Ser180Leu) for pneumococcal disease [13]. A study on patients with severe forms of tuberculosis, the rate of meningeal manifestations was associated with a synonymous TIRAP/Mal SNP, but not with the above mentioned variant [12]. Both investigations found an altered cytokine release in cell-stimulation assays, supporting the view that these SNPs are functionally relevant. Therefore, a second important finding of our study was the significantly increased risk for severe infections in TIRAP/Mal-homozygous patients. This supports previous findings of Khor and colleagues [13].

Although we could not observe a significant reduction in risk for TIRAP/Mal-heterozygous patients compared with WT-patients as seen in the Khor and colleagues study, comparison of homozygous and heterozygous patients was statistically different. As only one patient in Group II was TIRAP/Mal-homozygous, no comparison of patients was possible here.Activation of TLR4 may lead to a differential use of intracellular adaptors depending on the ligand that is bound to it [35]. Thus, a disturbance in the TLR4-TIRAP/Mal axis could lead to a predominant activation of the TIRAP/Mal-independent signaling pathway, which could explain the reduced release of nucleur factor (NF)-kB-dependent cytokines.

Therefore, a potential ‘shunting’ of signals via a second pathway (Trif/Tram) could result in an unbalanced cytokine release brought about by interferon regulatory factor 3 (IRF3) and the release of type I interferon-�� and -�� [36]. It has recently been shown that IRF3 is crucial for endotoxin tolerance and activation may result in a reduction of cytokine release upon Carfilzomib LPS-stimulation [36]. It is not known whether this may lead to a change in the clinical course of sepsis, but animal models showed an influence on sepsis mortality if IRF3 was pharmacologically inhibited [37].