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Variant IL-1 Receptor-Associated Kinase-1 Mediates Increased NF-B Activity¹

Department of Medicine, University of Alabama, Birmingham, AL 35294

IL-1R-associated kinase (IRAK)-1 is a critical mediator of TLR/IL-1R-induced activation of the transcription factor NF-B. 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-B 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-B activation. We found increased NF-B transcriptional activity and expression of NF-B-dependent proinflammatory cytokines in IL-1-stimulated IRAK-1-deficient cells transfected with variant IRAK-1 as compared with IRAK-1 wild type. IB- degradation was faster and p65 phosphorylation more prolonged after IL-1 stimulation in cells expressing the IRAK-1 variant. However, IL-1-induced activation of MAPKs and nuclear translocation of NF-B 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-B activation and inflammatory responses in individuals with this IRAK-1 haplotype.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL62221 and HL068743.

² Address correspondence and reprint requests to Dr. Edward Abraham, Department of Medicine, University of Alabama, School of Medicine, 420 Boshell Building, 1808 7th Avenue South, Birmingham, AL 35294. E-mail address: eabraham{at}uab.edu

³ Abbreviations used in this paper: TIR, TLR- and IL-1R-related; CBP, CREB-binding protein; HEK, human embryonic kidney; IKK, IB kinase; IRAK, IL-1R-associated kinase; SNP, single nucleotide polymorphism; TAB, TAK1-binding protein; TAK, TGF--activated kinase; TK, thymidine kinase; TRAF, TNFR-associated factor; WT, wild type.