Skip NavigationSkip to Content

Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections

  1. Author:
    Medvedev, A. E.
    Lentschat, A.
    Kuhns, D. B.
    Blanco, J. C. G.
    Salkowski, C.
    Zhang, S. L.
    Arditi, M. H.
    Gallin, J. I.
    Vogel, S. N.
  2. Author Address

    Univ Maryland, Dept Microbiol & Immunol, 655 W Baltimore St,Rm 13-009, Baltimore, MD 20101 USA Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA Sci Applicat Int Corp Frederick Inc, Natl Canc Inst Frederick, Clin Serv Program, Frederick, MD 21702 USA Cedars Sinai Med Ctr, Div Pediat Infect Dis, Los Angeles, CA 90048 USA NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA Vogel SN Univ Maryland, Dept Microbiol & Immunol, 655 W Baltimore St,Rm 13-009, Baltimore, MD 20101 USA
    1. Year: 2003
  1. Journal: Journal of Experimental Medicine
    1. 198
    2. 4
    3. Pages: 521-531
  2. Type of Article: Article
  1. Abstract:

    We identified previously a patient with recurrent bacterial infections who failed to respond to gram-negative LPS in vivo, and whose leukocytes were profoundly hyporesponsive to LPS and IL-1 in vitro. We now demonstrate that this patient also exhibits deficient responses in a skin blister model of aseptic inflammation. A lack of IL-18 responsiveness, coupled with diminished LPS and/or IL-1-induced nuclear factor-kappaB and activator protein-1 translocation, p38 phosphorylation, gene expression, and dysregulated IL-lR-associated kinase (IRAK)-1 activity in vitro support the hypothesis that the defect lies within the signaling pathway common to toll-like receptor 4, IL-1R, and IL-18R. This patient expresses a "compound heterozygous" genotype, with a point mutation (C877T in cDNA) and a two-nucleotide, AC deletion (620-621del in cDNA) encoded by distinct alleles of the IRAK-4 gene (GenBank/EMBL/DDBJ accession nos. AF445802 and AY186092). Both mutations encode proteins with an intact death domain, but a truncated kinase domain, thereby precluding expression of full-length IRAK-4 (i.e., a recessive phenotype). When overexpressed in HEK293T cells, neither truncated form augmented endogenous IRAK-1 kinase activity, and both inhibited endogenous IRAK-1 activity modestly. Thus, IRAK-4 is pivotal in the development of a normal inflammatory response initiated by bacterial or nonbacterial insults.

    See More

External Sources

  1. No sources found.

Library Notes

  1. No notes added.
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel