Please use this identifier to cite or link to this item: https://doi.org/10.3389/fmolb.2021.740650
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dc.titleMolecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts
dc.contributor.authorWidjaja, Anissa A
dc.contributor.authorViswanathan, Sivakumar
dc.contributor.authorJinrui, Dong
dc.contributor.authorSingh, Brijesh K
dc.contributor.authorTan, Jessie
dc.contributor.authorTing, Joyce Goh Wei
dc.contributor.authorLamb, David
dc.contributor.authorShekeran, Shamini G
dc.contributor.authorGeorge, Benjamin L
dc.contributor.authorSchafer, Sebastian
dc.contributor.authorCarling, David
dc.contributor.authorAdami, Eleonora
dc.contributor.authorCook, Stuart A
dc.date.accessioned2022-06-08T07:52:53Z
dc.date.available2022-06-08T07:52:53Z
dc.date.issued2021-09-28
dc.identifier.citationWidjaja, Anissa A, Viswanathan, Sivakumar, Jinrui, Dong, Singh, Brijesh K, Tan, Jessie, Ting, Joyce Goh Wei, Lamb, David, Shekeran, Shamini G, George, Benjamin L, Schafer, Sebastian, Carling, David, Adami, Eleonora, Cook, Stuart A (2021-09-28). Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts. FRONTIERS IN MOLECULAR BIOSCIENCES 8. ScholarBank@NUS Repository. https://doi.org/10.3389/fmolb.2021.740650
dc.identifier.issn2296889X
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/226747
dc.description.abstractIn fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signaling pathways downstream of IL11, which acts via IL6ST, are contentious with both STAT3 and ERK implicated. Here we dissect IL11 signaling in fibroblasts and study IL11-dependent protein synthesis pathways in the context of approved anti-fibrotic drug mechanisms of action. We show that IL11-induced ERK activation drives fibrogenesis and while STAT3 phosphorylation (pSTAT3) is also seen, this appears unrelated to fibroblast activation. Ironically, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, increases pSTAT3 in Il11ra1 null mouse fibroblasts. Unexpectedly, inhibition of STAT3 was found to induce severe proteotoxic ER stress, generalized fibroblast dysfunction and cell death. In contrast, inhibition of ERK prevented fibroblast activation in the absence of ER stress. IL11 stimulated an axis of ERK/mTOR/P70RSK protein translation and its selectivity for Collagen 1 synthesis was ascribed to an EPRS-regulated, ribosome stalling mechanism. Surprisingly, the anti-fibrotic drug nintedanib caused dose-dependent ER stress and lesser pSTAT3 expression. Pirfenidone had no effect on ER stress whereas anti-IL11 specifically inhibited the ERK/mTOR axis while reducing ER stress. These studies define the translation-specific signaling pathways downstream of IL11, intersect immune and metabolic signaling and reveal unappreciated effects of nintedanib.
dc.language.isoen
dc.publisherFRONTIERS MEDIA SA
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectBiochemistry & Molecular Biology
dc.subjectinterleukin-11
dc.subjectsignaling
dc.subjectfibrosis
dc.subjectfibroblasts
dc.subjectnintedanib
dc.subjectIL11
dc.subjectIL11RA
dc.subjectENDOPLASMIC-RETICULUM STRESS
dc.subjectACTIVATION
dc.subjectNINTEDANIB
dc.subjectINHIBITOR
dc.subjectFIBROSIS
dc.subjectGROWTH
dc.subjectBETA
dc.subjectERK
dc.typeArticle
dc.date.updated2022-06-07T05:24:48Z
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.3389/fmolb.2021.740650
dc.description.sourcetitleFRONTIERS IN MOLECULAR BIOSCIENCES
dc.description.volume8
dc.published.statePublished
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