Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming
Abstract Lameness is a common condition in dairy cattle caused by infectious or noninfectious agents. Joint lesions are the second most common cause of lameness and can be diagnosed in association with the presentation of digit injuries. Fibroblast-like synoviocyte (FLS) are predominant cells of syn...
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| Format: | Article |
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Nature Portfolio
2023-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-29851-y |
| _version_ | 1797864652496961536 |
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| author | Carolina Manosalva Pablo Alarcon John Quiroga Stefanie Teuber Maria D. Carretta Hedie Bustamante Rodrigo Lopez-Muñoz Maria A. Hidalgo Rafael A. Burgos |
| author_facet | Carolina Manosalva Pablo Alarcon John Quiroga Stefanie Teuber Maria D. Carretta Hedie Bustamante Rodrigo Lopez-Muñoz Maria A. Hidalgo Rafael A. Burgos |
| author_sort | Carolina Manosalva |
| collection | DOAJ |
| description | Abstract Lameness is a common condition in dairy cattle caused by infectious or noninfectious agents. Joint lesions are the second most common cause of lameness and can be diagnosed in association with the presentation of digit injuries. Fibroblast-like synoviocyte (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the expression of proinflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is a potent proinflammatory cytokine involved in cyclooxygenase 2 (COX-2) and proinflammatory cytokine expression in FLS. Previously, TNF-α was demonstrated to increase hypoxia-inducible Factor 1 (HIF-1), a transcription factor that rewires cellular metabolism and increases the expression of interleukin (IL)-6 in bovine FLS (bFLS). Despite this, the proinflammatory effects of TNF-α in bFLS on metabolic reprogramming have been poorly studied. We hypothesized that TNF-α increases glycolysis and in this way controls the expression of IL-6, IL-8, and COX-2 in bFLS. Results first, gas chromatography/mass spectrometry (GC/MS)-based untargeted metabolomics revealed that bTNF-α altered the metabolism of bFLS, increasing glucose, isoleucine, leucine, methionine, valine, tyrosine, and lysine and decreasing malate, fumarate, α-ketoglutarate, stearate, palmitate, laurate, aspartate, and alanine. In addition, metabolic flux analysis using D-glucose-13C6 demonstrated an increase of pyruvate and a reduction in malate and citrate levels, suggesting a decreased flux toward the tricarboxylic acid cycle after bTNF-α stimulation. However, bTNF-α increased lactate dehydrogenase subunit A (LDHA), IL-6, IL-8, IL-1β and COX-2 expression, which was dependent on glycolysis and the PI3K/Akt pathway. The use of FX11 and dichloroacetate (DCA), an inhibitor of LDHA and pyruvate dehydrogenase kinase (PDK) respectively, partially reduced the expression of IL-6. Our results suggest that bTNF-α induces metabolic reprogramming that favors glycolysis in bFLS and increases IL-6, IL-8, IL-1β and COX-2/PGE2. |
| first_indexed | 2024-04-09T22:56:28Z |
| format | Article |
| id | doaj.art-b6a4ffa837bd4096bbf2097fce8d8c7d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T22:56:28Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
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| spelling | doaj.art-b6a4ffa837bd4096bbf2097fce8d8c7d2023-03-22T11:16:27ZengNature PortfolioScientific Reports2045-23222023-02-0113111510.1038/s41598-023-29851-yBovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogrammingCarolina Manosalva0Pablo Alarcon1John Quiroga2Stefanie Teuber3Maria D. Carretta4Hedie Bustamante5Rodrigo Lopez-Muñoz6Maria A. Hidalgo7Rafael A. Burgos8Institute of Pharmacy, Faculty of Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileVeterinary Clinical Sciences Institute, Faculty of Veterinary Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileLaboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de ChileAbstract Lameness is a common condition in dairy cattle caused by infectious or noninfectious agents. Joint lesions are the second most common cause of lameness and can be diagnosed in association with the presentation of digit injuries. Fibroblast-like synoviocyte (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the expression of proinflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is a potent proinflammatory cytokine involved in cyclooxygenase 2 (COX-2) and proinflammatory cytokine expression in FLS. Previously, TNF-α was demonstrated to increase hypoxia-inducible Factor 1 (HIF-1), a transcription factor that rewires cellular metabolism and increases the expression of interleukin (IL)-6 in bovine FLS (bFLS). Despite this, the proinflammatory effects of TNF-α in bFLS on metabolic reprogramming have been poorly studied. We hypothesized that TNF-α increases glycolysis and in this way controls the expression of IL-6, IL-8, and COX-2 in bFLS. Results first, gas chromatography/mass spectrometry (GC/MS)-based untargeted metabolomics revealed that bTNF-α altered the metabolism of bFLS, increasing glucose, isoleucine, leucine, methionine, valine, tyrosine, and lysine and decreasing malate, fumarate, α-ketoglutarate, stearate, palmitate, laurate, aspartate, and alanine. In addition, metabolic flux analysis using D-glucose-13C6 demonstrated an increase of pyruvate and a reduction in malate and citrate levels, suggesting a decreased flux toward the tricarboxylic acid cycle after bTNF-α stimulation. However, bTNF-α increased lactate dehydrogenase subunit A (LDHA), IL-6, IL-8, IL-1β and COX-2 expression, which was dependent on glycolysis and the PI3K/Akt pathway. The use of FX11 and dichloroacetate (DCA), an inhibitor of LDHA and pyruvate dehydrogenase kinase (PDK) respectively, partially reduced the expression of IL-6. Our results suggest that bTNF-α induces metabolic reprogramming that favors glycolysis in bFLS and increases IL-6, IL-8, IL-1β and COX-2/PGE2.https://doi.org/10.1038/s41598-023-29851-y |
| spellingShingle | Carolina Manosalva Pablo Alarcon John Quiroga Stefanie Teuber Maria D. Carretta Hedie Bustamante Rodrigo Lopez-Muñoz Maria A. Hidalgo Rafael A. Burgos Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming Scientific Reports |
| title | Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming |
| title_full | Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming |
| title_fullStr | Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming |
| title_full_unstemmed | Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming |
| title_short | Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming |
| title_sort | bovine tumor necrosis factor alpha increases il 6 il 8 and pge2 in bovine fibroblast like synoviocytes by metabolic reprogramming |
| url | https://doi.org/10.1038/s41598-023-29851-y |
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