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IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells

Artikel i vetenskaplig tidskrift
Författare D. J. Davidson
A. J. Currie
D. M. Bowdish
K. L. Brown
C. M. Rosenberger
R. C. Ma
Johan Bylund
P. A. Campsall
A. Puel
C. Picard
J. L. Casanova
S. E. Turvey
R. E. Hancock
R. S. Devon
D. P. Speert
Publicerad i J Immunol
Volym 177
Nummer/häfte 11
Sidor 8202-11
Publiceringsår 2006
Publicerad vid Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Sidor 8202-11
Språk en
Länkar www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord Amino Acid Sequence, Blotting, Western, Cytokines/biosynthesis, Extracellular Signal-Regulated MAP Kinases/immunology, Fibroblasts/*immunology, Gene Expression, Humans, Immune System Diseases/*genetics, Interleukin-1 Receptor-Associated Kinases/*genetics, Male, Molecular Sequence Data, Mutation, Myeloid Cells/*immunology, Myeloid Differentiation Factor 88/immunology, NF-kappa B/immunology, Pedigree, RNA, Messenger/analysis, Receptors, Interleukin-1/*immunology, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptors/*immunology, Transcription, Genetic
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

Innate immunodeficiency has recently been reported as resulting from the Q293X IRAK-4 mutation with consequent defective TLR/IL-1R signaling. In this study we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell type specificity and ligand specificity in defective IL-1R-associated kinase (IRAK)-4-deficient cellular responses, indicating differential roles for this protein in human PBMCs and primary dermal fibroblasts and in LPS, IL-1beta, and TNF-alpha signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-kappaB signaling and intact MyD88-independent signaling and propose that dysfunctional complex 1 (IRAK1/TRAF6/TAK1) signaling, as a consequence of IRAK-4 deficiency, generates specific defects in MAPK activation that could underpin this patient's innate immunodeficiency. These studies demonstrate the importance of studying primary human cells bearing a clinically relevant mutation; they underscore the complexity of innate immune signaling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory proinflammatory signaling to normal human innate immune responses and immunodeficiencies.

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