Long non-coding RNAs in the regulation of the immune response
Authors: James A. Heward, Mark A. Lindsay
Journal: Trends in Immunology (2014)

•Widespread changes in lncRNA expresssion are associated with the immune response.•lncRNAs regulate the inflammatory response following activation of innate immunity.•lncRNAs regulate T cell differentiation and migration.•The action of long non-coding RNAs is mediated via diverse mechanisms. It is increasingly clear that long non-coding RNAs (lncRNAs) regulate a variety biological responses, and that they do so by a diverse range of mechanisms. In the field of immunology, recent publications have shown widespread changes in the expression of lncRNAs during the activation of the innate immune response and T cell development, differentiation, and activation. These lncRNAs control important aspects of immunity such as production of inflammatory mediators, differentiation, and cell migration through regulating protein–protein interactions or via their ability to basepair with RNA and DNA. We review the current understanding of the mechanism of action of these immune-related lncRNAs, discuss their impact on physiological and pathological processes, and highlight important areas of inquiry at the intersection between immunology and lncRNA biology. It is increasingly clear that long non-coding RNAs (lncRNAs) regulate a variety biological responses, and that they do so by a diverse range of mechanisms. In the field of immunology, recent publications have shown widespread changes in the expression of lncRNAs during the activation of the innate immune response and T cell development, differentiation, and activation. These lncRNAs control important aspects of immunity such as production of inflammatory mediators, differentiation, and cell migration through regulating protein–protein interactions or via their ability to basepair with RNA and DNA. We review the current understanding of the mechanism of action of these immune-related lncRNAs, discuss their impact on physiological and pathological processes, and highlight important areas of inquiry at the intersection between immunology and lncRNA biology. The first draft of the human genome uncovered several surprises including the observation that exonic regions of protein-coding genes represented <2% of the genome. Although some of the remaining DNA plays a crucial role in the maintenance of DNA structure and regulation of mRNA expression (i.e., transcription binding sites, promoter and enhancer regions), subsequent studies have shown that a significant proportion is transcribed into 'non-coding RNAs' (ncRNAs). Indeed, the recent release of the Encyclopedia of DNA Elements (the 'ENCODE' project aims to catalogue all the functional elements in human DNA) has concluded that ∼80% of DNA is functional and, importantly, that the majority (∼62%) is transcribed into non-coding RNA (ncRNA) [1Djebali S. et al.Landscape of transcription in human cells.Nature. 2012; 489: 101-108Crossref PubMed Scopus (4007) Google Scholar, 2ENCODE Project ConsortiumAn integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (12282) Google Scholar]. However, the broad definition employed to identify functional/transcribed regions of DNA, which included an association with modified histones, methylated CpG dinucleotides or open chromatin, means this is likely to be an overestimate [3Doolittle W.F. Is junk DNA bunk? A critique of ENCODE.Proc. Natl. Acad. Sci. 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The microRNA (miRNA) family of short ncRNAs are best characterised and are known to induce mRNA degradation or block mRNA translation via the RNA interference pathway. By contrast, much less in known about lncRNAs although, in comparison with mRNAs, these are generally shorter in length, contain fewer albeit longer exons, and are expressed at lower levels (median is ∼10% of mRNAs) [1Djebali S. et al.Landscape of transcription in human cells.Nature. 2012; 489: 101-108Crossref PubMed Scopus (4007) Google Scholar, 5Derrien T. et al.The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression.Genome Res. 2012; 22: 1775-1789Crossref PubMed Scopus (4040) Google Scholar, 6Ulitsky I. Bartel D.P. lincRNAs: genomics, evolution, and mechanisms.Cell. 2013; 154: 26-46Abstract Full Text Full Text PDF PubMed Scopus (2128) Google Scholar]. lncRNAs also demonstrate low evolutionary sequence conservation, with estimates that only ∼15% of mouse protein-coding genes have homologues in humans, leading to speculation that the majority of lncRNAs are non-functional [6Ulitsky I. 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The most recent release from GenCode (version 19) has annotated ∼14 000 lncRNA genes in humans [5Derrien T. et al.The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression.Genome Res. 2012; 22: 1775-1789Crossref PubMed Scopus (4040) Google Scholar] although, given that many lncRNAs are expressed in a cell-, tissue-, and developmental stage-specific manner, this is likely to be a significant underestimate [1Djebali S. et al.Landscape of transcription in human cells.Nature. 2012; 489: 101-108Crossref PubMed Scopus (4007) Google Scholar, 10Khalil A.M. et al.Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 11667-11672Crossref PubMed Scopus (2470) Google Scholar]. Presently, lncRNAs are classified by their position relative to protein-coding mRNAs and comprise the long intergenic ncRNA (lincRNA), intronic lncRNA, antisense lncRNA, transcribed pseudogene lncRNAs, and enhancer RNA (eRNA) (Box 1). However, these arbitrary definitions will need refining in the light of the increasing volume of sequencing data and the accumulating information on lncRNA function and mechanism.Box 1Classification of lncRNAsWith limited information on their function and mechanism of action, lncRNAs are currently classified by their positions relative to protein-coding genes (Figure I). In general, most lncRNAs are transcribed by RNA polymerase II (RNAP II) and are therefore capped, polyadenylated and commonly spliced. Antisense lncRNAs are transcribed across the exons of protein-coding genes from the opposite strand [76Wight M. Werner A. The functions of natural antisense transcripts.Essays Biochem. 2013; 54: 91-101Crossref PubMed Google Scholar] whereas intronic lncRNAs are transcribed from intronic regions in either the sense or antisense orientation. The largest group are the intergenic lncRNAs (lincRNAs), that are located between protein-coding genes [32Guttman M. et al.Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.Nature. 2009; 458: 223-227Crossref PubMed Scopus (3478) Google Scholar, 77Cabili M.N. et al.Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses.Genes Dev. 2011; 15: 1915-1927Crossref Scopus (373) Google Scholar]. Two additional groups that could arguably be classified as lincRNAs are transcribed pseudogenes and enhancer RNAs (eRNAs). Transcribed pseudogenes arise when a gene loses the ability to produce a protein, either through mutation or inaccurate duplication [78Pink R.C. et al.Pseudogenes: pseudo-functional or key regulators in health and disease?.RNA. 2011; 17: 792-798Crossref PubMed Scopus (327) Google Scholar]. eRNAs are produced by either mono- and bidirectional transcription at intergenic enhancer regions and can be differentiated from other lincRNAs by the presence of high H3K4me1 marks in their promoter regions [61Mousavi K. et al.eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.Mol. Cell. 2013; 51: 606-617Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 79Heintzman N.D. et al.Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.Nat. Genet. 2007; 39: 311-318Crossref PubMed Scopus (2557) Google Scholar, 80Natoli G. Andrau J-C. Noncoding transcription at enhancers: general principles and functional models.Annu. Rev. Genet. 2012; 46: 1-19Crossref PubMed Scopus (305) Google Scholar]. This contrasts with the members of the antisense, intronic, intergenic, and pseudogene lncRNA families that are associated with epigenetic marks characteristic of protein-coding genes (i.e., high H3Kme3 in the promoter region). With limited information on their function and mechanism of action, lncRNAs are currently classified by their positions relative to protein-coding genes (Figure I). In general, most lncRNAs are transcribed by RNA polymerase II (RNAP II) and are therefore capped, polyadenylated and commonly spliced. Antisense lncRNAs are transcribed across the exons of protein-coding genes from the opposite strand [76Wight M. Werner A. The functions of natural antisense transcripts.Essays Biochem. 2013; 54: 91-101Crossref PubMed Google Scholar] whereas intronic lncRNAs are transcribed from intronic regions in either the sense or antisense orientation. The largest group are the intergenic lncRNAs (lincRNAs), that are located between protein-coding genes [32Guttman M. et al.Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.Nature. 2009; 458: 223-227Crossref PubMed Scopus (3478) Google Scholar, 77Cabili M.N. et al.Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses.Genes Dev. 2011; 15: 1915-1927Crossref Scopus (373) Google Scholar]. Two additional groups that could arguably be classified as lincRNAs are transcribed pseudogenes and enhancer RNAs (eRNAs). Transcribed pseudogenes arise when a gene loses the ability to produce a protein, either through mutation or inaccurate duplication [78Pink R.C. et al.Pseudogenes: pseudo-functional or key regulators in health and disease?.RNA. 2011; 17: 792-798Crossref PubMed Scopus (327) Google Scholar]. eRNAs are produced by either mono- and bidirectional transcription at intergenic enhancer regions and can be differentiated from other lincRNAs by the presence of high H3K4me1 marks in their promoter regions [61Mousavi K. et al.eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci.Mol. Cell. 2013; 51: 606-617Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 79Heintzman N.D. et al.Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.Nat. Genet. 2007; 39: 311-318Crossref PubMed Scopus (2557) Google Scholar, 80Natoli G. Andrau J-C. Noncoding transcription at enhancers: general principles and functional models.Annu. Rev. Genet. 2012; 46: 1-19Crossref PubMed Scopus (305) Google Scholar]. This contrasts with the members of the antisense, intronic, intergenic, and pseudogene lncRNA families that are associated with epigenetic marks characteristic of protein-coding genes (i.e., high H3Kme3 in the promoter region). There is now accumulating evidence that lncRNAs are important regulators of physiological and pathological responses [11Maass P.G. et al.Long non-coding RNA in health and disease.J. Mol. Med. 2014; 92: 337-346Crossref PubMed Scopus (210) Google Scholar, 12Geisler S. Coller J. RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts.Nat. Rev. Mol. Cell Biol. 2013; 14: 699-712Crossref PubMed Scopus (1191) Google Scholar]. However, their potential importance in the immune response is only now emerging and it is this question that represents the topic of this review. As described in the forthcoming sections, immune-related lncRNAs are generally identified through examination of differential expression in response to activation of immune cells. This provides the basis for the subsequent functional and mechanistic analysis of individual lncRNAs. For clarity, these individual lncRNAs will be reviewed under the headings of innate immunity, acquired immunity, host–pathogen interaction, and enhancer RNAs. However, before proceeding it is worth highlighting emerging trends surrounding the mechanism of action of these immune-related lncRNAs. An interesting observation from the sequencing data is that many of the immune-related lncRNAs are located close to, or partially overlapping, the 5′ end (upstream) or 3′ end (downstream) of protein-coding genes implicated (and differentially expressed) in the immune response [13IIott N.E. et al.Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.Nat. Commun. 2014; 5: 3979Crossref PubMed Scopus (247) Google Scholar, 14Hu G. et al.Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation.Nat. Immunol. 2013; 14: 1190-1198Crossref PubMed Scopus (348) Google Scholar]. These are commonly transcribed in the antisense direction (relative to the protein-coding gene) which, in the case of upstream lncRNAs, can produce bidirectional transcription of the lncRNA and mRNA from a shared promoter region. Confusingly, these are often termed antisense lncRNAs despite there being only partial or no overlap with protein-coding genes and, as a result, we have recently proposed that these should instead be classified as mRNA-flanking lncRNAs (mf-lncRNAs) [13IIott N.E. et al.Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.Nat. Commun. 2014; 5: 3979Crossref PubMed Scopus (247) Google Scholar]. Given their locations, this group of lncRNAs which include THRIL (TNFα and hnRNPL related immunoregulatory lincRNA) [15Li Z. et al.The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL.Proc. Natl. Acad. Sci. U.S.A. 2013; 111: 1002-1007Crossref PubMed Scopus (510) Google Scholar], PACER (p50-associated COX-2 extragenic RNA) [16Krawczyk M. Emerson B.M. p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes.Elife. 2014; 3: e01776Crossref Scopus (249) Google Scholar], lincR-Ccr2-5′AS [14Hu G. et al.Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation.Nat. Immunol. 2013; 14: 1190-1198Crossref PubMed Scopus (348) Google Scholar], lnc-IL7R [17Cui H. et al.The human long noncoding RNA lnc-IL7R regulates the inflammatory response.Eur. J. Immunol. 2014; 44: 2085-2095Crossref PubMed Scopus (171) Google Scholar], and IL1β-RBT46 [13IIott N.E. et al.Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.Nat. Commun. 2014; 5: 3979Crossref PubMed Scopus (247) Google Scholar], have been shown to regulate the expression of their adjacent protein-coding gene in cis. eRNAs have also been demonstrated to control expression of protein-coding genes in cis, although chromatin looping is thought to be responsible for bringing the distal enhancer regions into close proximity with the promoter regions. The majority of the remaining immune-related lncRNAs, which are located in intergenic regions, regulate the immune response in trans. In addition to their cis actions, the four mRNA-flanking lncRNAs THRIL [15Li Z. et al.The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL.Proc. Natl. Acad. Sci. U.S.A. 2013; 111: 1002-1007Crossref PubMed Scopus (510) Google Scholar], lincR-Ccr2-5′AS [14Hu G. et al.Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation.Nat. Immunol. 2013; 14: 1190-1198Crossref PubMed Scopus (348) Google Scholar], lnc-IL7R [17Cui H. et al.The human long noncoding RNA lnc-IL7R regulates the inflammatory response.Eur. J. Immunol. 2014; 44: 2085-2095Crossref PubMed Scopus (171) Google Scholar], and IL1β-RBT46 [13IIott N.E. et al.Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.Nat. Commun. 2014; 5: 3979Crossref PubMed Scopus (247) Google Scholar] have also been shown regulate the expression of multiple additional genes in trans. As with proteins, it is speculated that lncRNAs are composed of domains that permit either protein binding and/or base-pairing with RNA or DNA sequences [18Yang L. et al.Long noncoding RNAs: fresh perspectives into the RNA world.Trends Biochem. Sci. 2014; 39: 35-43Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 19Tay Y. et al.The multilayered complexity of ceRNA crosstalk and competition.Nature. 2014; 505: 344-352Crossref PubMed Scopus (3027) Google Scholar, 20Rinn J.L. Chang H.Y. Genome regulation by long noncoding RNAs.Annu. Rev. Biochem. 2012; 81: 145-166Crossref PubMed Scopus (3326) Google Scholar, 21Wang K.C. Chang H.Y. Molecular mechanisms of long noncoding RNAs.Mol. Cell. 2011; 43: 904-914Abstract Full Text Full Text PDF PubMed Scopus (3595) Google Scholar, 22Ørom U.A. Shiekhattar R. Long noncoding RNAs usher in a new era in the biology of enhancers.Cell. 2013; 154: 1190-1193Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar]. Presently, it would appear that the action of most immune-related lncRNAs is mediated through protein binding. Targets include splicing factor proline/glutamine rich (SFPQ) [23Imamura K. et al.Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli.Mol. Cell. 2014; 53: 393-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar], importin-β family [24Willingham A.T. et al.A strategy for probing the function of noncoding RNAs finds a repressor of NFAT.Science. 2005; 309: 1570-1573Crossref PubMed Scopus (651) Google Scholar], and the transcription factors, nuclear factor-κB (NF-κB) [16Krawczyk M. Emerson B.M. p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes.Elife. 2014; 3: e01776Crossref Scopus (249) Google Scholar, 25Rapicavoli N.A. et al.A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics.Elife. 2013; 2: e00762Crossref Scopus (408) Google Scholar], signal transducer and activator of transcription 3 (STAT3) [26Wang P. et al.The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation.Science. 2014; 344: 310-313Crossref PubMed Scopus (877) Google Scholar], and the glucocorticoid receptor (GR) [27Kino T. et al.Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor.Sci. Signal. 2010; 3: ra8Crossref PubMed Scopus (1051) Google Scholar]. In these known examples, lncRNAs have been shown to act as 'decoys' to prevent protein–DNA binding (SFQR, NF-κB, and GR) or as antagonists of protein–protein interactions (importin-β and STAT3). Immune-related lncRNAs have also been shown to interact with members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family [15Li Z. et al.The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL.Proc. Natl. Acad. Sci. U.S.A. 2013; 111: 1002-1007Crossref PubMed Scopus (510) Google Scholar, 28Carpenter S. et al.A long noncoding RNA mediates both activation and repression of immune response genes.Science. 2013; 341: 789-792Crossref PubMed Scopus (785) Google Scholar] and components of chromatin-modifying complexes including the polycomb repressor complex 2 (PRC2) [29Rossetto C.C. et al.Regulation of viral and cellular gene expression by Kaposi's sarcoma-associated herpesvirus polyadenylated nuclear RNA.J. Virol. 2013; 87: 5540-5553Crossref PubMed Scopus (104) Google Scholar], WD repeat domain 5 (WDR5), a core subunit of the MLL methyltransferase complex [30Gomez J.A. et al.The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γ locus.Cell. 2013; 152: 743-754Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar], and the UTX/JMJD3 demethylases [31Rossetto C.C. Pari G. KSHV PAN RNA associates with demethylases UTX and JMJD3 to activate lytic replication through a physical interaction with the virus genome.PLoS Pathog. 2012; 8: e1002680Crossref PubMed Scopus (122) Google Scholar]. Although the exact mechanism is undefined, it has been speculated that they might act as scaffolds to bring together proteins and/or target these to the DNA through base-pairing, a situation that has been described with other chromatin-associated lncRNAs [12Geisler S. Coller J. RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts.Nat. Rev. Mol. Cell Biol. 2013; 14: 699-712Crossref PubMed Scopus (1191) Google Scholar]. The first evidence of a potential role for lncRNAs in the innate immune response was a report by Guttman et al. [32Guttman M. et al.Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.Nature. 2009; 458: 223-227Crossref PubMed Scopus (3478) Google Scholar] who used the intergenic deposition of epigenetic marks to identify 20 lincRNAs induced in lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived dendritic cells (BMDD). Microarray and RNA sequencing (RNA-Seq) have now demonstrated differential lncRNA expression following activation of monocytes, macrophages, dendritic cells, and fibroblasts, as well as following viral infection in mouse lungs [15Li Z. et al.The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL.Proc. Natl. Acad. Sci. U.S.A. 2013; 111: 1002-1007Crossref PubMed Scopus (510) Google Scholar, 25Rapicavoli N.A. et al.A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics.Elife. 2013; 2: e00762Crossref Scopus (408) Google Scholar, 26Wang P. et al.The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation.Science. 2014; 344: 310-313Crossref PubMed Scopus (877) Google Scholar, 28Carpenter S. et al.A long noncoding RNA mediates both activation and repression of immune response genes.Science. 2013; 341: 789-792Crossref PubMed Scopus (785) Google Scholar, 33Peng X. et al.Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling.MBio. 2010; 1: e00206-e210Crossref Scopus (223) Google Scholar, 34Dave R.K. et al.Regulated expression of PTPRJ/CD148 and an antisense long noncoding RNA in macrophages by proinflammatory stimuli.PLoS ONE. 2013; 8: e68306Crossref PubMed Scopus (36) Google Scholar, 35Garmire L.X. et al.A global clustering algorithm to identify long intergenic non-coding RNA – with applications in mouse macrophages.PLoS ONE. 2011; 6: e24051Crossref PubMed Scopus (29) Google Scholar] (Table 1). As outlined in the following sections, investigators have then examined the role of individual lncRNAs in the innate immune response.Table 1Long non-coding RNAs implicated in the immune response.LncRNAModel systemObservationRefsInnate immune responseMultipleCoronavirus infection in mouse lungRNA-seq demonstrated widespread differential expression of lncRNAs following lung infection with severe acute respiratory syndrome coronavirus in four mouse strains (129/S1, CAST, PWK, and WSB)33Peng X. et al.Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling.MBio. 2010; 1: e00206-e210Crossref Scopus (223) Google ScholarMultipleLPS-stimulated mouse macrophagesIdentification of multiple lincRNAs and eRNAs using pol II and H3K36me3 epigenetic marks. Eight of 11 lincRNAs were validated by qRT-PCR35Garmire L.X. et al.A global clustering algorithm to identify long intergenic non-coding RNA – with applications in mouse macrophages.PLoS ONE. 2011; 6: e24051Crossref PubMed Scopus (29) Google ScholarLincRNA-Cox2LPS-stimulated mouse bone marrow-derived dendritic cellsIdentification of 20 lincRNAs including lincRNA-Cox2 using deposition of epigenetic marks of active transcription (H3K4me3 at their promoters and H3K36me3 within the transcribed region)32Guttman M. et al.Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.Nature. 2009; 458: 223-227Crossref PubMed Scopus (3478) Google ScholarLincRNA-Cox2Pam3CSK4-stimulated mouse bone marrow-derived macrophagesRevealed that lincRNA-Cox2 repressed the expression of 787 genes in non-stimulated cells and the increased expression of 713 genes following exposure to Pam3CSK4. The actions of lincRNA-Cox2 were mediated through interaction with hnRNP-A/B and hnRNP-A2/B128Carpenter S. et al.A long noncoding RNA mediates both activation and repression of immune response genes.Science. 2013; 341: 789-792Crossref PubMed Scopus (785) Google ScholarTHRILPam3CSK4-stimulated human monocytic THP-1 cellsMicroarray analysis identified 159 differentially expressed lincRNAs including down-regulation of antisense lncRNA THRIL (TNFα and hnRNPL related immunoregulatory lincRNA). THRIL was shown to regulate both basal and Pam3CSK4-stimulated gene expression through an interaction with hnRNPL15Li Z. et al.The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL.Proc. Natl. Acad. Sci. U.S.A. 2013; 111: 1002-1007Crossref PubMed Scopus (510) Google ScholarLetheTNFα-stimulated mouse embryonic fibroblastsRNA-seq identified 112 lncRNAs and 54 transcribed pseudogenes that were differentially expressed including Rps15a-ps4 (renamed Lethe). Lethe was induced in response to IL1β and dexamethasone and shown to interact and block the binding of the RelA (p65) subunit of NF-κB25Rapicavoli N.A. et al.A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics.Elife. 2013; 2: e00762Crossref Scopus (408) Google ScholarNEAT1Poly(IC)- or influenza-stimulated HeLa and human epithelial A549 cellsIncreased NEAT1 expression induced the formation of paraspeckle formation. Redistribution of SFPQ from the CXCL8 promoter to the paraspeckles following NEAT1 binding leads to increased CXCL8 expression23Imamura K. et al.Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli.Mol. Cell. 2014; 53: 393-406Abstract Full Text Full Text PDF PubMed Scopus (533) Google ScholarPtprj-as1LPS-stimulated mouse bone marrow-derived macrophagesInduced in response to LPS34Dave R.K. et al.Regulated expression of PTPRJ/CD148 and an antisense long noncoding RNA in macrophages by proinflammatory stimuli.PLoS ONE. 2013; 8: e68306Crossref PubMed Scopus (36) Google ScholarIL1β-RBT46 and IL1β-eRNALPS-stimulated human monocytes and monocytic THP-1 cellsRNA-seq identified 76 eRNAs, 40 lincRNAs, 65 antisense RNAs, and 35 regions of bidirectional transcription (RBTs) that are differentially expressed. IL1β-RBT46 and IL1β-eRNA were shown to regulate LPS-induced IL1β and CXCL8 expression13IIott N.E. et al.Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes.Nat. Commun. 2014; 5: 3979Crossref PubMed Scopus (247) Google ScholarUnnamedLPS-stimulated K562 leukemias cellsMultiple lncRNAs were located upstream of TNF and shown to negatively regulate TNF expression, possibly through binding to the transcriptional repressor, LRRFIP1 [leucine rich repeat (in FLII) interacting protein 1]81Shi L. et al.Noncoding RNAs and LRRFIP1 regulate TNF expression.J. Immunol. 2014; 192: 3057-3067Crossref PubMed Scopus (20) Google ScholarLnc-IL7RLPS-stimulated monocytic THP1 cellsLnc-IL7R is transcribed from the 3′-UTR of IL7R in the sense orientation. Induced following LPS stimulation and negatively regulates IL7R, IL8, IL-6, VCAM-1, and E-selectin expression, a process associated with diminished H3K27me3 levels17Cui H. et al.The human long noncoding RNA lnc-IL7R regulates the inflammatory response.Eur. J. Immunol. 2014; 44: 2085-2095Crossref PubMed Scopus (171) Google ScholarPACERPMA- and LPS-stimulated human U937 monocytic cell linePACER (p50-associated COX-2 extragenic RNA) is expressed upstream of the Cox2 promoter and positively regulates COX2 production. PACER binds to, and drives the release of, the repressive p50 dimer of NF-κB from the Cox2 promoter16Krawczyk M. Emerson B.M. p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-