title: A distal enhancer in Il12b is the target of transcriptional repression by the STAT3 pathway and requires the basic leucine zipper (B-ZIP) protein NFIL3.
abstract: Deregulated IL-12 and IL-23 production from activated myeloid lineage cells is a key driver of numerous T cell-dependent autoimmune and inflammatory diseases. IL-12 and IL-23 share a common p40 subunit encoded by Il12b, which is negatively regulated at the transcriptional level by the STAT3 (signal transducer and activator of transcription 3)-activating anti-inflammatory cytokine IL-10. We found that IL-10 targets an enhancer 10 kb upstream of the Il12b transcriptional start site. Within the enhancer, a single 10-bp site is required for the inhibitory effects of IL-10 and is bound by NFIL3 (nuclear factor, interleukin 3-regulated), a B-ZIP transcription factor. Myeloid cells lacking NFIL3 produce excessive IL-12p40 and increased IL-12p70. Thus, the STAT3-dependent expression of NFIL3 is a key component of a negative feedback pathway in myeloid cells that suppresses proinflammatory responses.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Qualls
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Brien
authors.forename: Liza
authors.initials: L
authors.lastname: Balouzian
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
authors.forename: Stacey
authors.initials: S
authors.lastname: Schultz-Cherry
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C556062:IL10 protein, mouse; D053762:Interleukin-12 Subunit p40; C497441:Nfil3 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10