Abstract 12518: CTB-41I6.2 Is a Novel Human-Specific Long Noncoding RNA That Positively Regulates LPS-Induced IL6 Expression in Monocytes.

Introduction: Understanding tissue level transcriptome responses to activation of innate immunity in humans drives novel mechanistic insights and therapeutics. Long intergenic noncoding RNAs (lincRNAs) show tissue-specific expression patterns, supporting their potential roles in regulating localized responses in inflammatory disorders. Hypothesis: Novel human lincRNAs regulate monocyte- and adipose tissue-specific inflammatory responses to lipopolysaccharide (LPS). Methods and Results: We performed an inpatient endotoxin challenge (1 ng/kg LPS) in healthy humans to induce inflammation. We examined the transcriptome change of CD14+ monocytes (n=15) and adipose tissue (n=25) via RNA-seq. Differential expression (DE) analysis showed that among the 261 and 42 DE lincRNAs post-LPS in monocytes and adipose tissue, respectively (fold change ≥ 2, FDR < 0.05), only 9 overlapped, suggesting a divergent tissue-specific transcriptome response to endotoxemia. CTB-41I6.2 , a monocyte-enriched lincRNA not expressed in mouse, is one of the top DE lincRNAs specifically in monocytes but not in adipose tissue. To study the functional impact of CTB-41I6.2 , we used antisense oligonucleotide to knockdown CTB-41I6.2 in THP-1 monocytes and found reduced LPS-induced IL6 expression (Figure), but no effects on other inflammatory genes, including TNF , CCL5 , CXCL9 , and CCR7. Nuclear/cytosolic fractionation supported that CTB-41I6.2 is expressed in both compartments and knockdown did not affect the expression of cis -genes. Knockdown of CTB-41I6.2 also led to reduced CD86 mRNA at baseline without LPS stimulation. As CD86 engagement has been implicated to positively regulate IL-6 production, CTB-41I6.2 may modulate IL6 expression through a CD86-dependent manner. Conclusions: CTB-41I6.2 is a novel monocyte-enriched lincRNA that represents monocyte-specific in vivo response to endotoxemia and acts as a positive regulator of LPS-induced IL6 expression. [ABSTRACT FROM AUTHOR]