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Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0002-1617-334X
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Physiotherapy.ORCID iD: 0009-0001-1276-4644
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Physiotherapy.ORCID iD: 0000-0002-6091-3982
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.ORCID iD: 0000-0002-7906-9152
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 19, article id 11073Article in journal (Refereed) Published
Abstract [en]

Interleukin-1 (IL-1) and transforming growth factor-beta (TGFβ) are important cytokines involved in corneal wound healing. Here, we studied the effect of these cytokines on corneal stromal cell (keratocyte) differentiation. IL-1β treatment resulted in reduced keratocyte phenotype, as evident by morphological changes and decreased expression of keratocyte markers, including keratocan, lumican, ALDH3A1, and CD34. TGFβ1 treatment induced keratocyte differentiation towards the myofibroblast phenotype. This was inhibited by simultaneous treatment with IL-1β, as seen by inhibition of α-SMA expression, morphological changes, and reduced contractibility. We found that the mechanism of crosstalk between IL-1β and TGFβ1 occurred via regulation of the NF-κB signaling pathway, since the IL-1β induced inhibition of TGFβ1 stimulated keratocyte-myofibroblast differentiation was abolished by a specific NF-κB inhibitor, TPCA-1. We further found that Smad7 participated in the downstream signaling. Smad7 expression level was negatively regulated by IL-1β and positively regulated by TGFβ1. TPCA-1 treatment led to an overall upregulation of Smad7 at mRNA and protein level, suggesting that NF-κB signaling downregulates Smad7 expression levels in keratocytes. All in all, we propose that regulation of cell differentiation from keratocyte to fibroblast, and eventually myofibroblast, is closely related to the opposing effects of IL-1β and TGFβ1, and that the mechanism of this is governed by the crosstalk of NF-κB signaling.

Place, publisher, year, edition, pages
MDPI, 2022. Vol. 23, no 19, article id 11073
Keywords [en]
corneal wound healing, IL-1, keratocyte, NF-κB, TGFβ
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-200563DOI: 10.3390/ijms231911073ISI: 000867737100001PubMedID: 36232373Scopus ID: 2-s2.0-85139931390OAI: oai:DiVA.org:umu-200563DiVA, id: diva2:1718789
Funder
Swedish Research Council, 2017-01138Stiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadade, 2013/10Umeå UniversityRegion Västerbotten, RV-930288Available from: 2022-12-13 Created: 2022-12-13 Last updated: 2023-10-18Bibliographically approved

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Zhou, XinLi, JunhongBackman, Ludvig J.Danielson, Patrik

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