Thousands of large intergenic noncoding RNAs (lincRNAs) have been identified in the mammalian genome, many of which have important roles in regulating a variety of biological processes. Here, we used a custom microarray to identify lincRNAs associated with activation of the innate immune response. A panel of 159 lincRNAs was found to be differentially expressed following innate activation of THP1 macrophages. Among them, linc1992 was shown to be expressed in many human tissues and was required for induction of TNFα expression. Linc1992 bound specifically to heterogenous nuclear ribonucleoprotein L (hnRNPL) and formed a functional linc1992–hnRNPL complex that regulated transcription of the TNFα gene by binding to its promoter. Transcriptome analysis revealed that linc1992 was required for expression of many immune-response genes, including other cytokines and transcriptional and posttranscriptional regulators of TNFα expression, and that knockdown of linc1992 caused dysregulation of these genes during innate activation of THP1 macrophages. Therefore, we named linc1992 THRIL (TNFα and hnRNPL related immunoregulatory LincRNA). Finally, THRIL expression was correlated with the severity of symptoms in patients with Kawasaki disease, an acute inflammatory disease of childhood. Collectively, our data provide evidence that lincRNAs and their binding proteins can regulate TNFα expression and may play important roles in the innate immune response and inflammatory diseases in humans. Significance Genome-wide identification of changes in the expression of large intergenic noncoding RNAs (lincRNAs) in a classical model of innate immune cell activation revealed a panel of 159 lincRNAs that were highly modulated in stimulated THP1 macrophages. One of the lincRNAs, named TNFα and heterogenous nuclear ribonucleoprotein L (hnRNPL) related immunoregulatory LincRNA (THRIL), was essential for induction of TNFα, functions through a ribonucleoprotein (RNP) complex with hnRNPL, and plays an important role as regulator of physiological and pathological inflammatory immune responses.

The majority of febrile children have self-resolving viral infection, but a small proportion have life-threatening bacterial infections. Although culture of bacteria from normally sterile sites remains the gold standard for confirming bacterial infection, culture results may take several days and are frequently negative when infection resides in inaccessible sites or when antibiotics have been previously administered.^1-3 Current practice is to admit ill-appearing febrile children to the hospital and administer parenteral antibiotics while awaiting culture results.^4-6 Because only a minority of febrile children are ultimately proven to have bacterial infection, the process of ruling out bacterial infection results in a major burden on health care resources and in inappropriate antibiotic prescription.⁷

We report the isolation of a novel antimicrobial peptide, bass hepcidin, from the gill of hybrid striped bass, white bass (Morone chrysops) × striped bass (M. saxatilis). After the intraperitoneal injection of Micrococcus luteus and Escherichia coli, the peptide was purified from HPLC fractions with antimicrobial activity against Escherichia coli. Sequencing by Edman degradation revealed a 21‐residue peptide (GCRFCCNCCPNMSGCGVCCRF) with eight putative cysteines. Molecular mass measurements of the native peptide and the reduced and alkylated peptide confirmed the sequence with four intramolecular disulfide bridges. Peptide sequence homology to human hepcidin and other predicted hepcidins, indicated that the peptide is a new member of the hepcidin family. Nucleotide sequences for cDNA and genomic DNA were determined for white bass. A predicted prepropeptide (85 amino acids) consists of three domains: a signal peptide (24 amino acids), prodomain (40 amino acids) and a mature peptide (21 amino acids). The gene has two introns and three exons. A TATA box and several consensus‐binding motifs for transcription factors including C/EBP, nuclear factor‐κB, and hepatocyte nuclear factor were found in the region upstream of the transcriptional start site. In white bass liver, hepcidin gene expression was induced 4500‐fold following challenge with the fish pathogen, Streptococcus iniae, while expression levels remained low in all other tissues tested. A novel antimicrobial peptide from the gill, bass hepcidin, is predominantly expressed in the liver and highly inducible by bacterial exposure.