PMID- 33662027
OWN - NLM
STAT- MEDLINE
DCOM- 20211015
LR  - 20211204
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 16
IP  - 3
DP  - 2021
TI  - Differential responses to folic acid in an established keloid fibroblast cell 
      line are mediated by JAK1/2 and STAT3.
PG  - e0248011
LID - 10.1371/journal.pone.0248011 [doi]
LID - e0248011
AB  - Keloids are a type of disordered scar formation which not only show heterogeneity 
      between individuals and within the scar itself, but also share common features of 
      hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as 
      well as altered expression of the molecular markers of wound healing. Numerous 
      reports have established that cells from keloid scars display Warburg 
      metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly 
      dividing cells in which glycolysis becomes the predominant source of ATP over 
      oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along 
      with cells from patients with STAT3 loss of function (STA3 LOF; autosomal 
      dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the 
      hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. 
      Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid 
      fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by 
      further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 
      (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure 
      recapitulated the exaggerated closure and hyper-glycolytic state of keloid 
      fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional 
      studies are needed before extrapolating from a representative cell line to 
      keloids writ large, our results provide novel insights into the metabolic 
      consequences of STAT3 dysfunction, suggest a possible role for folate metabolism 
      in the pathogenesis of keloid scars, and offer in vitro pre-clinical data 
      supporting considerations of clinical trials for ruxolitinib in keloid disorder.
FAU - McCann, Katelyn J
AU  - McCann KJ
AD  - Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, 
      Maryland, United States of America.
FAU - Yadav, Manoj
AU  - Yadav M
AD  - Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, 
      Maryland, United States of America.
AD  - Epithelial Therapeutics Unit, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, Maryland, United States of America.
FAU - Alishahedani, Mohammadali E
AU  - Alishahedani ME
AD  - Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, 
      Maryland, United States of America.
AD  - Epithelial Therapeutics Unit, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, Maryland, United States of America.
FAU - Freeman, Alexandra F
AU  - Freeman AF
AD  - Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, 
      Maryland, United States of America.
FAU - Myles, Ian A
AU  - Myles IA
AUID- ORCID: 0000-0001-9316-3703
AD  - Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, 
      Maryland, United States of America.
AD  - Epithelial Therapeutics Unit, Laboratory of Clinical Immunology and Microbiology, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, Maryland, United States of America.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20210304
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Nitriles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 12001-76-2 (Vitamin B Complex)
RN  - 82S8X8XX8H (ruxolitinib)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.7.10.2 (JAK1 protein, human)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 1)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Cells, Cultured
MH  - Fibroblasts/*drug effects/metabolism/pathology
MH  - Folic Acid/*pharmacology
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Janus Kinase 1/antagonists & inhibitors/metabolism
MH  - Janus Kinase 2/antagonists & inhibitors/metabolism
MH  - Keloid/drug therapy/*metabolism/pathology
MH  - Nitriles
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyrazoles/*pharmacology
MH  - Pyrimidines
MH  - STAT3 Transcription Factor/metabolism
MH  - Signal Transduction/drug effects
MH  - Vitamin B Complex/*pharmacology
PMC - PMC7932104
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/03/05 06:00
MHDA- 2021/10/16 06:00
PMCR- 2021/03/04
CRDT- 2021/03/04 17:14
PHST- 2021/01/12 00:00 [received]
PHST- 2021/02/17 00:00 [accepted]
PHST- 2021/03/04 17:14 [entrez]
PHST- 2021/03/05 06:00 [pubmed]
PHST- 2021/10/16 06:00 [medline]
PHST- 2021/03/04 00:00 [pmc-release]
AID - PONE-D-21-01168 [pii]
AID - 10.1371/journal.pone.0248011 [doi]
PST - epublish
SO  - PLoS One. 2021 Mar 4;16(3):e0248011. doi: 10.1371/journal.pone.0248011. 
      eCollection 2021.