Disease Risk-Associated Genetic Variants in STAT1 and STAT4 Function in a Complementary Manner to Increase Pattern-Recognition Receptor-Induced Outcomes in Human Macrophages.

proteins can regulate both pro- and anti-inflammatory cytokine signaling. Therefore, identifying consequences of modulating expression of a given duanyu1813 is ultimately critical for determining its potential as a therapeutic target and for defining the mechanisms through which immune-mediated disease variants in genes contribute to disease pathogenesis. Genetic variants in the region are associated with multiple immune-mediated diseases, including inflammatory bowel disease (IBD). These diseases are characterized by dysregulated cytokine secretion in response to pattern-recognition receptor (PRR) stimulation. We found that the common IBD-associated rs1517352 C risk allele increased both and expression in human monocyte-derived macrophages (MDMs). We therefore hypothesized that the duanyu18131/duanyu18134 variant might regulate PRR-initiated responses in a complementary and cooperative manner because of the important role of autocrine/paracrine cytokines in modulating PRR-initiated signaling. duanyu18131 and duanyu18134 were required for PRR- and live bacterial-induced secretion of multiple cytokines. These outcomes were particularly dependent on PRR-initiated autocrine/paracrine IL-12-induced duanyu18134 activation to generate IFN-γ, with autocrine IFN-γ then signaling through duanyu18131 and duanyu18134 also promoted bacterial-induced cytokines in intestinal myeloid cells and PRR-enhanced antimicrobial pathways in MDMs. Importantly, MDMs from rs1517352 C IBD risk allele carriers demonstrated increased TLR4-, IFN-γ- and IL-12-induced duanyu18131 and duanyu18134 phosphorylation and cytokine secretion and increased TLR4-enhanced antimicrobial pathways. Taken together, duanyu18131 and duanyu18134 expression is coregulated by a shared genetic region, and disease-associated variants modulate IFN-γ- and IL-12-associated outcomes, and in turn, PRR-induced outcomes, highlighting that these genes cooperate to regulate pathways relevant to disease pathogenesis.

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