Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2

Tae Hwan Kim, Ursula Payne, Xiang Zhang, Yoichi Iwanaga, Michael P. Davey, James T. Rosenbaum, Robert D. Inman

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Blau syndrome (BS) is a rare familial granulomatous disease manifested by uveitis, arthritis and skin rash. BS has recently been found to be associated with a distinctive mutation in NOD2, which encodes an intracellular toll-like receptor. We have compared host cell interaction with bacterial challenge in U937 cells expressing wild type human NOD2 (NOD2wt), mutant NOD2 (NOD2Blau), or a vector control (VC). The cells were incubated with Salmonella typhimurium. Intracellular uptake was assessed by harvesting the cells at different time points following invasion and quantitating the CFU, recovered after gentamicin treatment to kill extracellular organisms. Expression of TNF-α, TLR2 and TLR4 was determined by semi-quantitative RT-PCR under resting conditions and after stimulation by bacteria. Invasion of target cells with S. typhimurium was diminished in the presence of NOD2Blau. Expression of TNF-α mRNA was enhanced following bacterial invasion in all cell lines but NOD2Blau was associated with a more rapid decline in TNF-α expression. Kinetics of intracellular clearance of bacteria indicated a relative defect in NOD2Blau compared to controls. This clearance defect may be related to the lack of sustained TNF-α seen in the early stages. These events were not related to differential TLR2 or TLR4 expression since there were no significant differences seen between the cell lines after bacterial stimulation. Our findings indicate that the NOD2 mutation associated with this syndrome alters host:microbial interaction, and this may have relevance to triggering factors in the ocular and joint inflammation seen in BS.

Original languageEnglish (US)
Pages (from-to)257-262
Number of pages6
JournalRheumatology International
Volume27
Issue number3
DOIs
StatePublished - Jan 1 2007

Keywords

  • Blau syndrome
  • NOD

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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