title: Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections.
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-1R-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.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD 20101, USA.
authors.forename: Andrei E
authors.initials: AE
authors.lastname: Medvedev
authors.forename: Arnd
authors.initials: A
authors.lastname: Lentschat
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: Jorge C G
authors.initials: JC
authors.lastname: Blanco
authors.forename: Cindy
authors.initials: C
authors.lastname: Salkowski
authors.forename: Shuling
authors.initials: S
authors.lastname: Zhang
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.forename: John I
authors.initials: JI
authors.lastname: Gallin
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000328:Adult; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases