Monocytes/macrophages are important in orchestrating inflammatory responses. However, knowledge of the long noncoding RNA (lncRNA) regulation of monocytic cell differentiation and diseases remains limited. We aimed to elucidate the role of the 17 kb lncRNA noncoding transcript in T cells ( ) in monocyte functions. Knockdown and chromatin immunoprecipitation (ChIP) assays in THP-1 cells (human monocytic leukemia cell line) revealed that is regulated by the monocyte key transcription factor C/EBPβ and that it binds to the promoter of nearby gene via hnRNP-U. Overexpression of in THP-1 cells resulted in cell cycle G1 arrest, differentiation into macrophages, a marked increase in and mRNA levels, and upregulation of the costimulatory molecules. In contrast to the downregulated observed in lipopolysaccharide (LPS)-treated THP-1 cells, the axis was found to be hyperactivated in peripheral blood mononuclear cells (PBMCs) of first-time diagnosed untreated early rheumatoid arthritis (RA) patients, and their gene expression levels decreased markedly after treatment. Higher initial expression levels were associated with a trend of higher disease activity DAS28 scores. In conclusion, our study suggests that the lncRNA is a regulator of inflammation in monocytes, and its activation participates in monocyte/macrophage differentiation and the pathogenesis of RA.