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Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements

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dc.contributor.authorMillrine, D.
dc.contributor.authorCardus Figueras, A.
dc.contributor.authorUceda Fernandez, J.
dc.contributor.authorAndrews, R.
dc.contributor.authorSzomolay, B.
dc.contributor.authorCossins, B.C.
dc.contributor.authorRice, C.M.
dc.contributor.authorLi, J.
dc.contributor.authorTyrrell, V.J.
dc.contributor.authorMcLeod, L.
dc.contributor.authorHolmans, P.
dc.contributor.authorO’Donnell, V.B.
dc.contributor.authorTaylor, P.R.
dc.contributor.authorTurner, S.J.
dc.contributor.authorJenkins, B.J.
dc.contributor.authorJones, G.W.
dc.contributor.authorTopley, N.
dc.contributor.authorWilliams, N.M.
dc.contributor.authorJones, S.A.
dc.date.issued2023
dc.description.abstractCytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, antimicrobial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues from mice during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focused on the transcriptional signature of the immunomodulatory cytokine IL-6 in both settings and examined how profibrotic IFN-y-secreting CD4+ T cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting antimicrobial immunity and tissue homeostasis. The introduction of IFN-y-secreting CD4+ T cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent IFN-g activation site motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T cells retune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.
dc.description.statementofresponsibilityDavid Millrine, Ana Cardus Figueras, Javier Uceda Fernandez, Robert Andrews, Barbara Szomolay, Benjamin C. Cossins, Christopher M. Rice, Jasmine Li, Victoria J. Tyrrell, Louise McLeod, Peter Holmans, Valerie B. O, Donnell, Philip R. Taylor, Stephen J. Turner, Brendan J. Jenkins, Gareth W. Jones, Nicholas Topley, Nigel M. Williams, and Simon A. Jones
dc.identifier.citationJournal of Immunology, 2023; 211(2):274-286
dc.identifier.doi10.4049/jimmunol.2300114
dc.identifier.issn0022-1767
dc.identifier.issn1550-6606
dc.identifier.orcidJenkins, B.J. [0000-0002-7552-4656]
dc.identifier.urihttps://hdl.handle.net/2440/140883
dc.language.isoen
dc.publisherThe American Association of Immunologists
dc.relation.grantNHMRC
dc.rightsCopyright©2023 The Authors. This article is distributed under the terms of the CC BY4.0Unported license.
dc.source.urihttps://doi.org/10.4049/jimmunol.2300114
dc.subjectCytokines
dc.subject.meshTh1 Cells
dc.subject.meshAnimals
dc.subject.meshMice
dc.subject.meshInflammation
dc.subject.meshRetroelements
dc.subject.meshInterleukin-6
dc.subject.meshCytokines
dc.subject.meshSTAT Transcription Factors
dc.subject.meshSTAT1 Transcription Factor
dc.subject.meshSTAT3 Transcription Factor
dc.titleTh1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements
dc.typeJournal article
pubs.publication-statusPublished

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