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2014 ; 192
(12
): 5924-32
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The IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1
expression and signaling through innate receptor-initiated pathways
#MMPMID24842757
Hedl M
; Zheng S
; Abraham C
J Immunol
2014[Jun]; 192
(12
): 5924-32
PMID24842757
show ga
Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis.
Consistently, a dysregulated increase or decrease in pattern-recognition receptor
(PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel
disease. Multiple gene loci are associated with inflammatory bowel disease, but
their functional effects are largely unknown. One such region in chromosome 2q12
(rs917997), also associated with other immune-mediated diseases, encompasses
IL18RAP. We found that human monocyte-derived macrophages (MDMs) from rs917997 AA
risk carriers secrete significantly less cytokines than G carriers upon
stimulation of multiple PRRs, including nucleotide-binding oligomerization domain
2 (NOD2). We identified that IL-18 signaling through IL-18RAP was critical in
amplifying PRR-induced cytokine secretion in MDMs. IL-18RAP responded to
NOD2-initiated early, caspase-1-dependent autocrine IL-18, which dramatically
enhanced MAPK, NF-?B, PI3K, and calcium signaling. Reconstituting MAPK activation
was sufficient to rescue decreased cytokines in NOD2-stimulated
IL-18RAP-deficient MDMs. Relative to GG carriers, MDM from rs917997 AA carriers
had decreased expression of cell-surface IL-18RAP protein, as well as of IL-18R1
and IL-1R1, genes also located in the IL18RAP region. Accordingly, these
risk-carrier MDMs show diminished PRR-, IL-18-, and IL-1-induced MAPK and NF-?B
signaling. Taken together, our results demonstrate clear functional consequences
of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function
through decreased IL-18RAP, IL-18R1, and IL-1R1 protein expression, which impairs
autocrine IL-18 and IL-1 signaling, thereby leading to decreased cytokine
secretion in MDMs upon stimulation of a broad range of PRRs.