The interleukin‐6 (IL6)–174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6

Abstract

Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6-174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL -1 ), followed by CG genotype (mean 1113 pg mL -1 ), and lowest in individuals with the CC genotype (mean 256 pg mL -1 ). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL -1 ) and patients with the IL6 CC genotype (555 pg mL -1 ) compared to patients with the -174 GG genotype (276 pg mL -1 ). In conclusion, the IL6-174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials.

Cytokine Gene Polymorphism in Idiopathic Nephrotic Syndrome Children

“…There are few studies on recurrent infections, thrombophilia and immunological alterations, such as celiac disease, breast cancer, systemic lupus erythromatosus and leishmaniasis [15,[24][25][26]. Our study revealed that CC genotype of IL-6-G174C is more prevalent in the INS patient, and steroid resistant group, hence may be considered responsible for progression as well as for steroid resistance.…”

“…1a, b and c) in accordance with Tischendorf et al [15], Kobayashi et al [16] and Wilson et al [17]. To improve the genotyping quality and validation, Random samples were reanalyzed, in a double blind manner to confirm the RFLP results.…”

IL6-174 G/C Gene Polymorphism in Children with Septicemia: Single Center Study

“…Tischendorf [19] demonstrated that a significantly lower frequency of the IL6-174 G/G genotype was associated with higher mortality in septic patients compared to surviving septic patients, that mean carriage the C allele put individuals at risk [19].…”

Host Genetics and Pediatric Sepsis

“…A common polymorphism located at position -174 in the promoter region is a G to C substitution, and in vitro studies demonstrate an association of the G allele with increased expression of IL-6 [139]. In addition, serum levels of IL-6 are lower in adults with sepsis with the C allele [140] and in healthy adults, the G allele is associated with higher basal serum levels of IL-6 [139]. In contrast, monocytes isolated from neonates with the C allele and stimulated with LPS produce more IL-6 than monocytes isolated from neonates with the G allele [141], the opposite of what is observed in adults.…”

“…A significantly lower frequency of the -174 GG genotype is associated with higher mortality in septic patients compared with surviving septic patients, suggesting that the GG genotype is in some fashion protective, or conversely carriage the C allele places individuals at risk. Indeed, in cohort of adult septic patients, the CC genotype was more frequent in those with shock [140]. Other SNPs also exist in the gene coding for IL-6 allowing for the analysis of haplotypes or combinations of various SNPs.…”