PMID- 36361504
OWN - NLM
STAT- MEDLINE
DCOM- 20221114
LR  - 20221117
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 21
DP  - 2022 Oct 22
TI  - Recombinant Human Proteoglycan 4 (rhPRG4) Downregulates TNFalpha-Stimulated NFkappaB 
      Activity and FAT10 Expression in Human Corneal Epithelial Cells.
LID - 10.3390/ijms232112711 [doi]
LID - 12711
AB  - Dry Eye Disease (DED) is a complex pathology affecting millions of people with 
      significant impact on quality of life. Corneal inflammation, including via the 
      nuclear factor kappa B (NFkappaB) pathway, plays a key etiological role in DED. 
      Recombinant human proteoglycan 4 (rhPRG4) has been shown to be a clinically 
      effective treatment for DED that has anti-inflammatory effects in corneal 
      epithelial cells, but the underlying mechanism is still not understood. Our goal 
      was to understand if rhPRG4 affects tumor necrosis factor alpha (TNFalpha)-stimulated 
      inflammatory activity in corneal epithelial cells. We treated hTERT-immortalized 
      corneal epithelial (hTCEpi) cells +/- TNFalpha +/- rhPRG4 and performed Western blotting 
      on cell lysate and RNA sequencing. Bioinformatics analysis revealed that rhPRG4 
      had a significant effect on TNFalpha-mediated inflammation with potential effects on 
      matricellular homeostasis. rhPRG4 reduced activation of key inflammatory pathways 
      and decreased expression of transcripts for key inflammatory cytokines, 
      interferons, interleukins, and transcription factors. TNFalpha treatment 
      significantly increased phosphorylation and nuclear translocation of p65, and 
      rhPRG4 significantly reduced both these effects. RNA sequencing identified human 
      leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10), a ubiquitin-like 
      modifier protein which has not been studied in the context of DED, as a key 
      pro-inflammatory transcript increased by TNFalpha and decreased by rhPRG4. These 
      results were confirmed at the protein level. In summary, rhPRG4 is able to 
      downregulate NFkappaB activity in hTCEpi cells, suggesting a potential biological 
      mechanism by which it may act as a therapeutic for DED.
FAU - Menon, Nikhil G
AU  - Menon NG
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
FAU - Suhail, Yasir
AU  - Suhail Y
AUID- ORCID: 0000-0002-1296-9738
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
FAU - Goyal, Ruchi
AU  - Goyal R
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
FAU - Du, Wenqiang
AU  - Du W
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
FAU - Tanguay, Adam P
AU  - Tanguay AP
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
FAU - Jay, Gregory D
AU  - Jay GD
AD  - Department of Emergency Medicine, Warren Alpert Medical School, Brown University, 
      Providence, RI 02903, USA.
AD  - School of Engineering, Brown University, Providence, RI 02912, USA.
FAU - Ghosh, Mallika
AU  - Ghosh M
AD  - Department of Cell Biology, School of Medicine, UConn Health, Farmington, CT 
      06030, USA.
FAU - Kshitiz
AU  - Kshitiz
AUID- ORCID: 0000-0003-4241-9427
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
FAU - Schmidt, Tannin A
AU  - Schmidt TA
AUID- ORCID: 0000-0001-7140-254X
AD  - Biomedical Engineering Department, School of Dental Medicine, UConn Health, 
      Farmington, CT 06030, USA.
LA  - eng
GR  - NA/UConn Health Biomedical Engineering Department Startup Funds/
PT  - Journal Article
DEP - 20221022
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (NF-kappa B)
RN  - 0 (Proteoglycans)
SB  - IM
MH  - Humans
MH  - *Tumor Necrosis Factor-alpha/pharmacology
MH  - *NF-kappa B/metabolism
MH  - Quality of Life
MH  - Proteoglycans/metabolism
MH  - Epithelial Cells/metabolism
MH  - Inflammation
PMC - PMC9657836
OTO - NOTNLM
OT  - PRG4
OT  - corneal epithelial cells
OT  - dry eye
OT  - lubricin
OT  - proteoglycan 4
COIS- T.A.S., A.T. and G.J. have authored patents on rhPRG4. T.A.S. and G.J. hold 
      equity in Lubris BioPharma LLC, MA, USA. T.A.S. is also a paid consultant for 
      Lubris LLC, MA, USA. All other authors have nothing to disclose. The funders had 
      no role in the design of the study; in the collection, analyses, or 
      interpretation of data; in the writing of the manuscript, or in the decision to 
      publish the results.
EDAT- 2022/11/12 06:00
MHDA- 2022/11/15 06:00
PMCR- 2022/10/22
CRDT- 2022/11/11 01:23
PHST- 2022/09/27 00:00 [received]
PHST- 2022/10/15 00:00 [revised]
PHST- 2022/10/17 00:00 [accepted]
PHST- 2022/11/11 01:23 [entrez]
PHST- 2022/11/12 06:00 [pubmed]
PHST- 2022/11/15 06:00 [medline]
PHST- 2022/10/22 00:00 [pmc-release]
AID - ijms232112711 [pii]
AID - ijms-23-12711 [pii]
AID - 10.3390/ijms232112711 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Oct 22;23(21):12711. doi: 10.3390/ijms232112711.