5.4 Tumor necrosis factor beta (TNF-β)

TNF-β is a cytokine produced by T lymphocytes similar to TNF-α and binds to TNF receptors. It activates endothelial cells and neutrophils and is a mediator of

Infective Endocarditis: Inflammatory Response, Genetic Susceptibility, Oxidative Stress… DOI: http://dx.doi.org/10.5772/intechopen.84908

acute inflammatory response, providing a link between T-cell activation and inflammation. These effects are the same as those of TNF-α, consistent with their binding to the same receptors. However, as the quantity of TNF-β is much less than that of TNF-α made by lipopolysaccharide-stimulated mononuclear phagocytes, TNF-β is not readily detected in the circulation. For this reason, TNF-β is usually a local cytokine and not a mediator of systemic injury. A single nucleotide polymorphism has been found at position +252 in the first intron of the TNF-β gene and consists of a G in the wild-type allele (TNFB1) and an A in the variant allele (TNFB2). Known as the Nco1 polymorphism, it has been proposed as a potentially influential locus in many inflammatory conditions. Delongui et al. studied the association of the TNF-β Nco1 genetic polymorphism with susceptibility to sepsis in 60 patients diagnosed with sepsis and in 148 healthy blood donors. Among the septic patients, the allelic frequencies of TNFB1 and TNFB2 were 0.2833 and 0.7166, respectively, and they differed from those observed in the blood donors (p = 0.02). The TNFB2 allele frequency was higher in the septic patients than in the controls [OR = 1.65 (CI 95% 1.02–2.69), p = 0.0315], all this suggesting an implication in susceptibility to sepsis [52].

#### 5.5 Interleukin 10 (IL-10)

IL-10 has beneficial anti-inflammatory properties; however, an excess of IL-10 has been reported to induce immunosuppression in bacterial sepsis. Published data demonstrates that lower production of IL-10 from stimulated peripheral blood mononuclear cells (PBMC) from septic patients is significantly correlated with favorable disease outcome [53]. Stanilova et al. [54] investigated the ˜1082 (A/G) polymorphism in the promoter of the IL-10 gene by measuring IL-10 production from stimulated peripheral blood mononuclear cells (PBMC) and to evaluate the relationship of this polymorphism with susceptibility to severe sepsis and its outcome. They found that carriage of at least one copy of IL-10-1082 G allele in sepsis patients and in healthy controls resulted in a statistically significant increase in IL-10 production from stimulated PBMC. Patients who survived sepsis had a significant decrease of IL-10-1082 allele G frequency, compared with controls (17 vs. 47.2%; p = 0.012). This suggests that this genetic variation has an impact in IL-10 production and in the outcomes of septic patients [55].

#### 5.6 Interleukin-1 receptor antagonist gene (IL-1 Ra)

Interleukin 1β (IL-1β) is a potent pro-inflammatory cytokine implicated in the development of chronic inflammatory disorders. IL-1β signaling is blocked by IL-1 Ra, a natural regulator of IL-1 cytokines. IL-1 Ra binds to the IL-1 receptor and thereby prevents binding of both IL-1a and IL-1b [56]. F. Arnalich et al. aimed to determine the influence of the polymorphism within the intron 2 of the IL-1RNa (IL-RNa\*) on the outcome of severe sepsis. A group of 78 patients with severe sepsis (51 survivors and 27 non-survivors) was compared with a healthy control group of 130 blood donors and 56 patients with uncomplicated pneumonia. They found a significant association between IL-1RN\* polymorphism and survival. After adjusting for age and APACHE II score, they did a multiple logistic regression analysis that showed that patients' homozygotes for the allele \*2 had 6°47 times more risk of death (95% CI 1°01–41°47, p = 0.04). These authors concluded that these genetic mutations might be implicated in an increased risk of death in septic patients [57].
