Long noncoding RNAs (lncRNAs), once thought to be transcriptional noise, have been recently shown to regulate a variety of biological processes. However, there is not much knowledge regarding their roles in the inflammatory response. In this study, we performed human lncRNA microarray assays and identified a number of lncRNAs that demonstrated altered expression in response to LPS stimulation. Of these lncRNAs, lnc-IL7R, which overlaps with the 3′untranslated region (3′UTR) of the human interleukin-7 receptor α-subunit gene (IL7R) gene, was significantly upregulated in LPS-treated cells. Functionally, lnc-IL7R was capable of diminishing the LPS-induced inflammatory response, demonstrated by elevated expression of LPS-induced E-selectin, VCAM-1, IL-6, and IL-8 in lnc-IL7R knockdown cells. Mechanistically, we found that lnc-IL7R knockdown diminished trimethylation of histone H3 at lysine 27 (H3K27me3), a hallmark of silent transcription, at the proximal promoters of the inflammatory mediators. Our data suggest that lnc-IL7R contributes another layer of complexity in regulation of the inflammatory response. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.