PMID- 36828912
OWN - NLM
STAT- MEDLINE
DCOM- 20230228
LR  - 20230419
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Feb 24
TI  - Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine 
      fibroblast-like synoviocytes by metabolic reprogramming.
PG  - 3257
LID - 10.1038/s41598-023-29851-y [doi]
LID - 3257
AB  - 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-alpha) is a potent 
      proinflammatory cytokine involved in cyclooxygenase 2 (COX-2) and proinflammatory 
      cytokine expression in FLS. Previously, TNF-alpha 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-alpha in bFLS on metabolic 
      reprogramming have been poorly studied. We hypothesized that TNF-alpha 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-alpha altered the metabolism of bFLS, 
      increasing glucose, isoleucine, leucine, methionine, valine, tyrosine, and lysine 
      and decreasing malate, fumarate, alpha-ketoglutarate, stearate, palmitate, laurate, 
      aspartate, and alanine. In addition, metabolic flux analysis using 
      D-glucose-(13)C(6) demonstrated an increase of pyruvate and a reduction in malate 
      and citrate levels, suggesting a decreased flux toward the tricarboxylic acid 
      cycle after bTNF-alpha stimulation. However, bTNF-alpha increased lactate dehydrogenase 
      subunit A (LDHA), IL-6, IL-8, IL-1beta 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-alpha induces 
      metabolic reprogramming that favors glycolysis in bFLS and increases IL-6, IL-8, 
      IL-1beta and COX-2/PGE2.
CI  - (c) 2023. The Author(s).
FAU - Manosalva, Carolina
AU  - Manosalva C
AD  - Institute of Pharmacy, Faculty of Sciences, Universidad Austral de Chile, 
      Valdivia, Chile.
FAU - Alarcon, Pablo
AU  - Alarcon P
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
FAU - Quiroga, John
AU  - Quiroga J
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile. 
      john.quiroga@uach.cl.
FAU - Teuber, Stefanie
AU  - Teuber S
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
FAU - Carretta, Maria D
AU  - Carretta MD
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
FAU - Bustamante, Hedie
AU  - Bustamante H
AD  - Veterinary Clinical Sciences Institute, Faculty of Veterinary Sciences, 
      Universidad Austral de Chile, Valdivia, Chile.
FAU - Lopez-Munoz, Rodrigo
AU  - Lopez-Munoz R
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
FAU - Hidalgo, Maria A
AU  - Hidalgo MA
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
FAU - Burgos, Rafael A
AU  - Burgos RA
AD  - Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, 
      Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile. 
      rburgos1@uach.cl.
LA  - eng
SI  - figshare/10.6084/m9.figshare.20280363.v2
SI  - figshare/10.6084/m9.figshare.20264502.v1
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230224
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Interleukin-6)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - 0 (Interleukin-8)
RN  - 817L1N4CKP (malic acid)
RN  - 0 (Malates)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Cytokines)
SB  - IM
MH  - Cattle
MH  - Animals
MH  - *Synoviocytes/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Interleukin-6/metabolism
MH  - Synovial Membrane/pathology
MH  - Dinoprostone/metabolism
MH  - Interleukin-8/metabolism
MH  - Malates/metabolism
MH  - *Arthritis, Rheumatoid/pathology
MH  - Cyclooxygenase 2/metabolism
MH  - Lameness, Animal
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Cytokines/metabolism
MH  - Cells, Cultured
MH  - Fibroblasts/metabolism
PMC - PMC9958177
COIS- The authors declare no competing interests.
EDAT- 2023/02/25 06:00
MHDA- 2023/03/03 06:00
PMCR- 2023/02/24
CRDT- 2023/02/24 23:23
PHST- 2022/07/04 00:00 [received]
PHST- 2023/02/11 00:00 [accepted]
PHST- 2023/02/24 23:23 [entrez]
PHST- 2023/02/25 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2023/02/24 00:00 [pmc-release]
AID - 10.1038/s41598-023-29851-y [pii]
AID - 29851 [pii]
AID - 10.1038/s41598-023-29851-y [doi]
PST - epublish
SO  - Sci Rep. 2023 Feb 24;13(1):3257. doi: 10.1038/s41598-023-29851-y.