IMO-3100, an Antagonist of Toll-Like Receptors 7 and 9, Modulates Gene Expression and Regulatory Networks Induced by Ligands (48.25)

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Abstract In autoimmune diseases, immune complexes containing self-nucleic acids have been shown to induce inflammatory responses through TLR7 and 9. IMO-3100 is a novel DNA-based antagonist of TLR7 and 9 that is shown to inhibit TLR7- and 9-mediated immune responses. To elucidate inhibitory effects of IMO-3100 on TLR7 and 9 agonist-mediated gene expression, we treated human PBMCs with a TLR7 or TLR9 agonist with or without IMO-3100, isolated total RNA, carried out gene expression profiling on human inflammatory response and autoimmunity microarray, and analyzed data to identify changes in regulatory networks. IMO-3100 alone showed insignificant up-regulation of a small number of genes. TLR9 agonist significantly up-regulated a number of genes, including IP-10, MyD88, MCP-1, IL-6, IRF7, IL-17A, NF-κB1, and RIPK2, which regulate immune responses, NF-κB signaling, inflammation, and chemotaxis networks. TLR7 agonist showed a different gene expression profile compared with TLR9 agonist. The genes that were significantly up-regulated by TLR7 agonist include IP-10, IRF7, IFN-α1, IFN-α4, IFN-γ, IL-15Ra, IL-17A, IL-6, and TIRAP, which regulate host defense response, chemotaxis, and cytokine and chemokine signaling pathways. Co-incubation of IMO-3100 with either TLR agonist resulted in inhibition of genes that were up-regulated with either TLR agonist alone. These results indicate that TLR7 and 9 agonists induce different gene expression profiles and IMO-3100 is a potent inhibitor of these responses. IMO-3100 is a lead candidate identified for development for potential applications in autoimmune diseases.