TNFAIP2 Inhibits Early TNFα-Induced NF-x03BA;B Signaling and Decreases Survival in Septic Shock Patients.
During septic shock, tumor necrosis factor alpha (TNFα) is an early response gene and induces a plethora of genes and signaling pathways. To identify robust signals in genes reliably upregulated by TNFα, we first measured microarray gene expression in vitro and searched methodologically comparable, publicly available data sets to identify concordant signals. Using tag single-nucleotide polymorphisms in the genes common to all data sets, we identified a genetic variant of the TNFAIP2 gene, rs8126, associated with decreased 28-day survival and increased organ dysfunction in an adult cohort in the Vasopressin and Septic Shock Trial. Similar to this cohort, we found that an association with rs8126 and increased organ dysfunction is replicated in a second cohort of septic shock patients in the St. Paul's Hospital Intensive Care Unit. We found that TNFAIP2 inhibits NF-x03BA;B activity, impacting the downstream cytokine interleukin (IL)-8. The minor G allele of TNFAIP2 rs8126 resulted in greater TNFAIP2 expression, decreased IL-8 production and was associated with decreased survival in patients experiencing septic shock. These data suggest that TNFAIP2 is a novel inhibitor of NF-x03BA;B that acts as an autoinhibitor of the TNFα response during septic shock.
Department of Emergency and Surgery, Stanford University School of Medicine, Stanford, Calif., USA.
Simone A
SA
Thair
Elena
E
Topchiy
John H
JH
Boyd
Mihai
M
Cirstea
Catherine
C
Wang
Taka-Aki
TA
Nakada
Christopher D
CD
Fjell
Mark
M
Wurfel
James A
JA
Russell
Keith R
KR
Walley
D000328:Adult; D002170:Canada; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D066264:Datasets as Topic; D060005:Genotyping Techniques; D006801:Humans; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000276:immunology; D046228:Microarray Analysis; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D015398:Signal Transduction; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
C508606:CXCL8 protein, human; D016207:Cytokines; D016209:Interleukin-8; D016328:NF-kappa B; C085839:TNFAIP2 protein, human; D014409:Tumor Necrosis Factor-alpha