Long noncoding RNAs (lncRNAs) are emerging as major regulators of a variety of cell signaling processes. Many lncRNAs are expressed in immune cells and appear to play critical roles in the regulation of immune response. Here, we have investigated the potential role of a well-known lncRNA, HOTAIR, in inflammatory and immune response. Our studies demonstrate that HOTAIR expression is induced in immune cells (macrophages) upon treatment with lipopolysaccharide (LPS). Knockdown of HOTAIR reduces NF-κB-mediated inflammatory gene and cytokine expression in macrophages. Inhibition of NF-κB resulted in down-regulation of LPS-induced expression of HOTAIR as well as IL-6 and iNOS expression. We further demonstrated that HOTAIR regulates activation of NF-κB and its target genes (IL-6 and iNOS) expression via facilitating the degradation of IκBα. HOTAIR knockdown reduces the expression of NF-κB target gene expression via inhibiting the recruitment of NF-κB and associated cofactors at the target gene promoters. Taken together, our findings suggest that HOTAIR is a critical player in NF-κB activation in macrophages suggesting its potential functions in inflammatory and immune response.

Inflammation plays central roles in the immune response. Inflammatory response normally requires higher energy and therefore is associated with glucose metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF-kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in the regulation of glucose metabolism in immune cells during inflammation. Our results demonstrate that LPS-induced inflammation induces the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake in macrophages. LPS-induced Glut1 expression is regulated via NF-kB activation. Importantly, siRNA-mediated knockdown of HOTAIR suppressed the LPS-induced expression of Glut1 suggesting key roles of HOTAIR in LPS-induced Glut1 expression in macrophage. HOTAIR induces NF-kB activation, which in turn increases Glut1 expression in response to LPS. We also found that HOTAIR regulates glucose uptake in macrophages during LPS-induced inflammation and its knockdown decreases LPS-induced increased glucose uptake. HOTAIR also regulates other upstream regulators of glucose metabolism such as PTEN and HIF1α, suggesting its multimodal functions in glucose metabolism. Overall, our study demonstrated that lncRNA HOTAIR plays key roles in LPS-induced Glut1 expression and glucose uptake by activating NF-kB and hence HOTAIR regulates metabolic programming in immune cells potentially to meet the energy needs during the immune response.

HOXA5 is a homeobox-containing gene associated with the development of the lung, gastrointestinal tract, and vertebrae. Here, we investigate potential roles and the gene regulatory mechanism in HOXA5 in breast cancer cells. Our studies demonstrate that HOXA5 expression is elevated in breast cancer tissues and in estrogen receptor (ER)-positive breast cancer cells. HOXA5 expression is critical for breast cancer cell viability. Biochemical studies show that estradiol (E2) regulates HOXA5 gene expression in cultured breast cancer cells in vitro. HOXA5 expression is also upregulated in vivo in the mammary tissues of ovariectomized female rats. E2-induced HOXA5 expression is coordinated by ERs. Knockdown of either ERα or ERβ downregulated E2-induced HOXA5 expression. Additionally, ER co-regulators, including CBP/p300 (histone acetylases) and MLL-histone methylases (MLL2, MLL3), histone acetylation-, and H3K4 trimethylation levels are enriched at the HOXA5 promoter in present E2. In summary, our studies demonstrate that HOXA5 is overexpressed in breast cancer and is transcriptionally regulated via estradiol in breast cancer cells.

Inflammation plays a central role in immune response and the inflammatory response is closely linked with metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF‐kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in regulation of glucose metabolism in immune cells during inflammation. Our study demonstrate that lncRNA HOTAIR regulates the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake into macrophages. SiRNA‐mediated knockdown of HOTAIR suppressed the LPS‐induced expression of Glut1 and glucose update in macrophages suggesting key roles of HOTAIR in LPS‐induced Glut1 expression and glucose metabolism. HOTAIR induces NF‐kB activation which in turn increases Glut1 expression and glucose metabolism in response to LPS. Beyond HOTAIR, we also discovered several novel lncRNAs (termed as LinfRNA: Long‐noncoding inflammation associated RNA) which are closely associated with inflammation and metabolism. Overall, our study demonstrated that HOTAIR and LinfRNAs play key roles in NF‐kB activation and inflammation and regulate metabolic programming in immune cells potentially to meet the energy needs at the priming of immune response to pathogenic infection or other stressors. Support or Funding Information National Institute of Health grant # 1R15 ES019129‐01

The mammalian immune system orchestrates innate and adaptive immune responses that are complex biochemical processes regulated by various protein and lipid mediators such as cytokines, chemokines, hormones, growth factors, and others. The emerging evidences suggest that non‐coding RNAs (ncRNAs) play vital roles in regulation of immune responses. In a recent study, we discovered that lncRNA HOTAIR plays critical roles in immune response and inflammation. HOTAIR expression is induced in immune cells (macrophages) upon treatment with lipopolysaccharide (LPS) or peptidoglycan, which are components of bacterial cell membrane. HOTAIR is required for LPS‐induced expression of cytokines and pro‐inflammatory genes. HOTAIR regulates activation of NF‐κB and its target gene (IL‐6 and iNOS) expression via facilitating the degradation of IκBα. Thus, HOTAIR appear to be a critical player in NF‐κB activation in macrophages suggesting its potential functions in inflammatory and immune response. Beyond HOTAIR, we also performed RNA‐Seq analysis on macrophages and identified novel lncRNA associated with immune response and inflammation. Overall, lncRNA appear to be play critical roles in immune response and inflammation and are misregulated in inflammatory disease.Support or Funding InformationNational Institute of Health‐ 1R15HL142032This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.