Abstract
IntroductionVariations in genetic background are the leading cause of differential susceptibility to traumatic infection. Heat shock protein 90 (HSP90), a broadly distributed and conserved molecule, regulates inflammation under stressful and traumatic conditions. However, the relationships between HSP90 genetic polymorphisms, post-traumatic inflammatory responses and organ function remain unknown.MethodsA total of 286 healthy volunteers and patients with severe trauma took part in a single nucleotide polymorphism (SNP)-based analysis of the HSP90beta gene and a clinical association analysis. HSP90beta and TNF-alpha levels were determined using quantitative PCR and western blot. The transcriptional activity of the HSP90beta promoter was assayed using the Dual-Luciferase Reporter Assay System.ResultsThe minor allele frequencies for the SNP located at −144 bp relative to the HSP90beta transcriptional start site were 28.47% and 28.52% in the normal and trauma populations, respectively; no significant differences were found between these two distributions. However, the results showed that a promoter containing the -144A allele had a higher transcriptional activity than did a promoter containing the wild-type -144C allele. Furthermore, the -144A promoter induced high expression of HSP90beta and low expression of the inflammatory factor TNF-alpha in a lipopolysaccharide-induced inflammatory model. A clinical association analysis showed that the multiple organ dysfunction scores for -144AA genotype carriers were significantly lower than those of -144CC carriers following trauma. No significant correlations were found between the presence of the two alleles and the incidence of sepsis.ConclusionsThese results indicate that differences in expression caused by the -144 polymorphism in the HSP90beta promoter are associated with cellular inflammatory responses and the severity of organ injury. These findings will aid in risk assessment and early prevention of complications for patients with severe trauma.
Highlights
Variations in genetic background are the leading cause of differential susceptibility to traumatic infection
We showed that BALB/c and C57BL/6 mice had different tolerances for trauma and that their HSP84 genes differed at several functional sites [23]; eliminating these genetic changes lessened or eliminated the differences in trauma tolerance between the two mouse strains, and we showed that these changes affected the activity of glucocorticoid receptor (GR), a client protein of Heat shock protein 90 (HSP90) [23]
The D9 values of the first 5 single nucleotide polymorphism (SNP) were greater than 0.95, indicating that they were closely linked with one another (Fig. 1)
Summary
Variations in genetic background are the leading cause of differential susceptibility to traumatic infection. Heat shock protein 90 (HSP90), a broadly distributed and conserved molecule, regulates inflammation under stressful and traumatic conditions. The relationships between HSP90 genetic polymorphisms, post-traumatic inflammatory responses and organ function remain unknown. Recent studies have indicated that HSP90, a widely expressed stress protein, plays an important regulatory role in a number of inflammatory signaling pathways. HSP90 regulates the expression of inflammatory factor TNF-alpha, IFNgamma, and IL-1 (via NF-kappaB), and it modulates the SAPK/JNK signaling pathway in lipopolysaccharide (LPS)induced inflammatory mouse models [10], [11]. Mutations in the HSP90 gene may play a more significant role than modulators involved in single inflammatory signaling pathways. Because the HSP90 protein is highly conserved and shows few differences between species, little research has been carried out regarding the effects of HSP90 mutations
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