Variant IL-1 receptor-associated kinase-1 mediates increased NF-kappa B activity.
IL-1R-associated kinase (IRAK)-1 is a critical mediator of TLR/IL-1R-induced activation of the transcription factor NF-kappaB. We previously described that a commonly occurring IRAK-1 variant haplotype, containing amino acid changes from serine to phenylalanine at position 196 and from leucine to serine at position 532, is associated with increased activation of NF-kappaB in LPS-stimulated neutrophils from patients with sepsis-induced acute lung injury and also higher mortality and more severe clinical outcomes in such patients. To investigate the underlying molecular mechanisms, we examined the ability of wild-type and variant IRAK-1 to modulate NF-kappaB activation. We found increased NF-kappaB transcriptional activity and expression of NF-kappaB-dependent proinflammatory cytokines in IL-1beta-stimulated IRAK-1-deficient cells transfected with variant IRAK-1 as compared with IRAK-1 wild type. IkappaB-alpha degradation was faster and p65 phosphorylation more prolonged after IL-1beta stimulation in cells expressing the IRAK-1 variant. However, IL-1-induced activation of MAPKs and nuclear translocation of NF-kappaB are comparable in both IRAK-1 variant- and IRAK-1 wild-type-expressing cells. Autophosphorylation of the IRAK-1 variant is greater than that found with wild-type IRAK-1. Additionally, variant IRAK-1 has greater interaction with TNFR-associated factor 6 than does wild-type IRAK-1. The enhanced activity of variant IRAK-1 appeared to be due to the alteration at aa 532, with only minimal effects being associated with change at aa 196. These results demonstrate that variant IRAK-1 is associated with alterations in multiple intracellular events that are likely to contribute to increased NF-kappaB activation and inflammatory responses in individuals with this IRAK-1 haplotype.
Liu
Gang
G
Department of Medicine, University of Alabama, Birmingham, AL 35294, USA.
Tsuruta
Yuko
Y
Gao
Zhiqian
Z
Park
Young-Jun
YJ
Abraham
Edward
E
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D018805:Sepsis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology*