<i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition
Background: Interleukin-11 (IL-11) is increased in patients with systemic sclerosis (SSc) and is thought to play a role in fibrosis. Many studies have reported decreased fibrosis when IL-11 is blocked, but few have examined factors that induce IL-11 expression. Because fibrosis has been linked to ac...
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MDPI AG
2024-10-01
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| Series: | Rheumato |
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| Online Access: | https://www.mdpi.com/2674-0621/4/4/13 |
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| author | Caya M. McFalls Lianne M. Connolly Alfred G. Fustakgi Carol M. Artlett |
| author_facet | Caya M. McFalls Lianne M. Connolly Alfred G. Fustakgi Carol M. Artlett |
| author_sort | Caya M. McFalls |
| collection | DOAJ |
| description | Background: Interleukin-11 (IL-11) is increased in patients with systemic sclerosis (SSc) and is thought to play a role in fibrosis. Many studies have reported decreased fibrosis when IL-11 is blocked, but few have examined factors that induce IL-11 expression. Because fibrosis has been linked to activated inflammasomes driving caspase-1 maturation and the secretion of IL-1β, we set out to determine if IL-11 expression was dependent on caspase-1 activity. Methods: Primary lung fibroblast cell lines derived from patients with SSc, IPF (fibrotic control), and healthy individuals were cultured at low passage. Gene expression for <i>IL-11</i> and the IL-11 receptor (<i>IL-11Rα1</i>) was analyzed using qPCR and normalized to the control, and collagen production was measured using Sirius Red. Results: SSc and IPF fibroblasts expressed significantly more <i>IL-11</i> transcripts than normal cells (3.35-fold and 9.97-fold more, <i>p</i> = 0.0396 and <i>p</i> = 0.0023, respectively). <i>IL-11Rα1</i> was expressed 2.32-fold and 2.27-fold more in SSc and IPF (<i>p</i> = 0.0004 and <i>p</i> = 0.0032, respectively) than in normal cells. In SSc fibroblasts, inhibition of caspase-1 with YVAD decreased <i>IL-11</i> expression by 49.59% (<i>p</i> = 0.0016) but did not affect <i>IL-11Rα1</i> expression (<i>p</i> > 0.05). <i>IL-11</i> expression was increased 2.97-fold with TGF-β1 (<i>p</i> = 0.0030) and 22.24-fold with IL-1β (<i>p</i> < 0.0001), while the expression of <i>IL-11Rα1</i> was not induced with these two cytokines. LPS increased <i>IL-11</i> expression in normal fibroblasts 1.52-fold (<i>p</i> = 0.0042), which was abolished with YVAD (<i>p</i> < 0.0001). <i>IL-11Rα1</i> gene transcripts were also increased with LPS 1.50-fold (<i>p</i> = 0.0132), but YVAD did not inhibit this expression. In these studies, we were unable to detect IL-11 protein nor were we able to induce <i>COL1A1</i> expression or increase the total amount of collagen secreted by fibroblasts with human recombinant IL-11. Conclusions: <i>IL-11</i> and its receptor, <i>IL-11Rα1</i>, are both elevated in fibrosis. <i>IL-11</i> expression is dependent on inflammasome activation of caspase-1 and the downstream cytokines TGF-β1 and IL-1β, while <i>IL-11Rα1</i> was only dependent on NF-kB. |
| format | Article |
| id | doaj-art-cb69d774cc3442ab92629f9f1650a725 |
| institution | Kabale University |
| issn | 2674-0621 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Rheumato |
| spelling | doaj-art-cb69d774cc3442ab92629f9f1650a7252024-12-27T14:51:41ZengMDPI AGRheumato2674-06212024-10-014416317510.3390/rheumato4040013<i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen DepositionCaya M. McFalls0Lianne M. Connolly1Alfred G. Fustakgi2Carol M. Artlett3Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USADepartment of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USADepartment of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USADepartment of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USABackground: Interleukin-11 (IL-11) is increased in patients with systemic sclerosis (SSc) and is thought to play a role in fibrosis. Many studies have reported decreased fibrosis when IL-11 is blocked, but few have examined factors that induce IL-11 expression. Because fibrosis has been linked to activated inflammasomes driving caspase-1 maturation and the secretion of IL-1β, we set out to determine if IL-11 expression was dependent on caspase-1 activity. Methods: Primary lung fibroblast cell lines derived from patients with SSc, IPF (fibrotic control), and healthy individuals were cultured at low passage. Gene expression for <i>IL-11</i> and the IL-11 receptor (<i>IL-11Rα1</i>) was analyzed using qPCR and normalized to the control, and collagen production was measured using Sirius Red. Results: SSc and IPF fibroblasts expressed significantly more <i>IL-11</i> transcripts than normal cells (3.35-fold and 9.97-fold more, <i>p</i> = 0.0396 and <i>p</i> = 0.0023, respectively). <i>IL-11Rα1</i> was expressed 2.32-fold and 2.27-fold more in SSc and IPF (<i>p</i> = 0.0004 and <i>p</i> = 0.0032, respectively) than in normal cells. In SSc fibroblasts, inhibition of caspase-1 with YVAD decreased <i>IL-11</i> expression by 49.59% (<i>p</i> = 0.0016) but did not affect <i>IL-11Rα1</i> expression (<i>p</i> > 0.05). <i>IL-11</i> expression was increased 2.97-fold with TGF-β1 (<i>p</i> = 0.0030) and 22.24-fold with IL-1β (<i>p</i> < 0.0001), while the expression of <i>IL-11Rα1</i> was not induced with these two cytokines. LPS increased <i>IL-11</i> expression in normal fibroblasts 1.52-fold (<i>p</i> = 0.0042), which was abolished with YVAD (<i>p</i> < 0.0001). <i>IL-11Rα1</i> gene transcripts were also increased with LPS 1.50-fold (<i>p</i> = 0.0132), but YVAD did not inhibit this expression. In these studies, we were unable to detect IL-11 protein nor were we able to induce <i>COL1A1</i> expression or increase the total amount of collagen secreted by fibroblasts with human recombinant IL-11. Conclusions: <i>IL-11</i> and its receptor, <i>IL-11Rα1</i>, are both elevated in fibrosis. <i>IL-11</i> expression is dependent on inflammasome activation of caspase-1 and the downstream cytokines TGF-β1 and IL-1β, while <i>IL-11Rα1</i> was only dependent on NF-kB.https://www.mdpi.com/2674-0621/4/4/13systemic sclerosisIL-11IL-11Rα1fibrosiscaspase-1 |
| spellingShingle | Caya M. McFalls Lianne M. Connolly Alfred G. Fustakgi Carol M. Artlett <i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition Rheumato systemic sclerosis IL-11 IL-11Rα1 fibrosis caspase-1 |
| title | <i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition |
| title_full | <i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition |
| title_fullStr | <i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition |
| title_full_unstemmed | <i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition |
| title_short | <i>IL-11</i> Expression in Systemic Sclerosis Is Dependent on Caspase-1 Activity but Does Not Increase Collagen Deposition |
| title_sort | i il 11 i expression in systemic sclerosis is dependent on caspase 1 activity but does not increase collagen deposition |
| topic | systemic sclerosis IL-11 IL-11Rα1 fibrosis caspase-1 |
| url | https://www.mdpi.com/2674-0621/4/4/13 |
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