PMID- 32470060
OWN - NLM
STAT- MEDLINE
DCOM- 20200909
LR  - 20200909
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 15
IP  - 5
DP  - 2020
TI  - Hypomethylation of IL1RN and NFKB1 genes is linked to the dysbalance in 
      IL1beta/IL-1Ra axis in female patients with type 2 diabetes mellitus.
PG  - e0233737
LID - 10.1371/journal.pone.0233737 [doi]
LID - e0233737
AB  - Inflammation has received considerable attention in the pathogenesis of type 2 
      diabetes mellitus (T2DM). Supporting this concept, enhanced expression of 
      interleukin (IL)-1beta and increased infiltration of macrophages are observed in 
      pancreatic islets of patients with T2DM. Although IL-1 receptor antagonist 
      (IL-1Ra) plays a major role in controlling of IL-1beta-mediated inflammation, its 
      counteraction effects and epigenetic alterations in T2DM are less studied. Thus, 
      we aimed to analyze the DNA methylation status in IL1RN, RELA (p65) and NFKB1 
      (p50) genes in peripheral blood mononuclear cells (PBMCs) from treated T2DM 
      patients (n = 35) and age-/sex- matched healthy controls (n = 31). Production of 
      IL-1beta and IL-1Ra was analyzed in plasma and supernatants from LPS-induced PBMCs. 
      Immunomodulatory effects of IL-1beta and IL-1Ra were studied on THP-1 cells. Average 
      DNA methylation level of IL1RN and NFKB1 gene promoters was significantly 
      decreased in T2DM patients in comparison with healthy controls (P< 0.05), which 
      was associated with the increased IL-1Ra (P< 0.001) and IL-1beta (P = 0.039) plasma 
      levels in T2DM patients. Negative association between average methylation of 
      IL1RN gene and IL-1Ra plasma levels were observed in female T2DM patients. 
      Methylation of NFKB1 gene was negatively correlated with IL-1Ra levels in the 
      patients and positively with IL-1beta levels in female patients. LPS-stimulated 
      PBMCs from female patients failed to raise IL-1beta production, while the cells from 
      healthy females increased IL-1beta production in comparison with unstimulated cells 
      (P< 0.001). Taken together, the findings suggest that hypomethylation of IL1RN 
      and NFKB1 gene promoters may promote the increased IL-1beta/IL-1Ra production and 
      regulate chronic inflammation in T2DM. Further studies are necessary to elucidate 
      the causal direction of these associations and potential role of IL-1Ra in 
      anti-inflammatory processes in treated patients with T2DM.
FAU - Margaryan, Sona
AU  - Margaryan S
AD  - Department of Immunology, Faculty of Medicine and Dentistry, Palacky University 
      and University Hospital Olomouc, Olomouc, Czech Republic.
AD  - Russian-Armenian (Slavonic) University, Yerevan, Armenia.
AD  - Institute of Molecular Biology, Laboratory of Molecular and Cellular Immunology, 
      Yerevan, Armenia.
FAU - Kriegova, Eva
AU  - Kriegova E
AD  - Department of Immunology, Faculty of Medicine and Dentistry, Palacky University 
      and University Hospital Olomouc, Olomouc, Czech Republic.
FAU - Fillerova, Regina
AU  - Fillerova R
AD  - Department of Immunology, Faculty of Medicine and Dentistry, Palacky University 
      and University Hospital Olomouc, Olomouc, Czech Republic.
FAU - Smotkova Kraiczova, Veronika
AU  - Smotkova Kraiczova V
AD  - Department of Immunology, Faculty of Medicine and Dentistry, Palacky University 
      and University Hospital Olomouc, Olomouc, Czech Republic.
FAU - Manukyan, Gayane
AU  - Manukyan G
AUID- ORCID: 0000-0001-7541-5743
AD  - Department of Immunology, Faculty of Medicine and Dentistry, Palacky University 
      and University Hospital Olomouc, Olomouc, Czech Republic.
AD  - Russian-Armenian (Slavonic) University, Yerevan, Armenia.
AD  - Institute of Molecular Biology, Laboratory of Molecular and Cellular Immunology, 
      Yerevan, Armenia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200529
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (IL1B protein, human)
RN  - 0 (IL1RN protein, human)
RN  - 0 (Interleukin 1 Receptor Antagonist Protein)
RN  - 0 (Interleukin-1beta)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (NFKB1 protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - DNA Methylation
MH  - Diabetes Mellitus, Type 2/*immunology/pathology
MH  - Female
MH  - Humans
MH  - Interleukin 1 Receptor Antagonist Protein/blood/*metabolism
MH  - Interleukin-1beta/*metabolism
MH  - Male
MH  - Middle Aged
MH  - NF-kappa B p50 Subunit/blood/*metabolism
MH  - Pancreatitis, Chronic/etiology/*immunology
MH  - THP-1 Cells
PMC - PMC7259508
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/05/30 06:00
MHDA- 2020/09/10 06:00
PMCR- 2020/05/29
CRDT- 2020/05/30 06:00
PHST- 2020/01/20 00:00 [received]
PHST- 2020/05/11 00:00 [accepted]
PHST- 2020/05/30 06:00 [entrez]
PHST- 2020/05/30 06:00 [pubmed]
PHST- 2020/09/10 06:00 [medline]
PHST- 2020/05/29 00:00 [pmc-release]
AID - PONE-D-20-01825 [pii]
AID - 10.1371/journal.pone.0233737 [doi]
PST - epublish
SO  - PLoS One. 2020 May 29;15(5):e0233737. doi: 10.1371/journal.pone.0233737. 
      eCollection 2020.