Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk
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 morp...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| author | Xin Zhou Junhong Li Ludvig J. Backman Patrik Danielson |
| author_facet | Xin Zhou Junhong Li Ludvig J. Backman Patrik Danielson |
| author_sort | Xin Zhou |
| collection | DOAJ |
| description | 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. |
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| id | doaj.art-b5d75f33d8644c77b6eab2ac5fde6693 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:43:22Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b5d75f33d8644c77b6eab2ac5fde66932023-11-23T20:26:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123191107310.3390/ijms231911073Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling CrosstalkXin Zhou0Junhong Li1Ludvig J. Backman2Patrik Danielson3Department of Integrative Medical Biology (IMB), Faculty of Medicine, Umeå University, 901 87 Umeå, SwedenDepartment of Integrative Medical Biology (IMB), Faculty of Medicine, Umeå University, 901 87 Umeå, SwedenDepartment of Integrative Medical Biology (IMB), Faculty of Medicine, Umeå University, 901 87 Umeå, SwedenDepartment of Integrative Medical Biology (IMB), Faculty of Medicine, Umeå University, 901 87 Umeå, SwedenInterleukin-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.https://www.mdpi.com/1422-0067/23/19/11073keratocyteNF-κBTGFβIL-1corneal wound healing |
| spellingShingle | Xin Zhou Junhong Li Ludvig J. Backman Patrik Danielson Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk International Journal of Molecular Sciences keratocyte NF-κB TGFβ IL-1 corneal wound healing |
| title | Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk |
| title_full | Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk |
| title_fullStr | Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk |
| title_full_unstemmed | Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk |
| title_short | Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk |
| title_sort | keratocyte differentiation is regulated by nf κb and tgfβ signaling crosstalk |
| topic | keratocyte NF-κB TGFβ IL-1 corneal wound healing |
| url | https://www.mdpi.com/1422-0067/23/19/11073 |
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