PMID- 25187563
OWN - NLM
STAT- MEDLINE
DCOM- 20150423
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 37
DP  - 2014 Sep 16
TI  - Impaired hydrogen sulfide synthesis and IL-10 signaling underlie 
      hyperhomocysteinemia-associated exacerbation of colitis.
PG  - 13559-64
LID - 10.1073/pnas.1413390111 [doi]
AB  - Vitamin B deficiencies, which can lead to hyperhomocysteinemia (Hhcy), are 
      commonly reported in patients with inflammatory bowel disease (IBD) and may be a 
      causative underlying factor. However, the mechanism for this effect is not known. 
      Hydrogen sulfide (H2S) is a gaseous mediator that promotes tissue repair and 
      resolution of inflammation. In experimental colitis, a marked increase in colonic 
      H2S synthesis drives ulcer healing and resolution of inflammation. Because H2S 
      synthesis is in part dependent upon enzymes that require vitamin B6 as a 
      cofactor, we tested the hypothesis that Hhcy in rodent models would increase the 
      susceptibility to colitis. In all three models tested, diet-induced Hhcy 
      significantly exacerbated colitis. The usual elevation of colonic H2S synthesis 
      after induction of colitis was absent in all three models of colitis. 
      Administration of an H2S donor to Hhcy rats significantly decreased the severity 
      of colitis. Compared with wild-type mice, interleukin (IL) 10-deficient mice on a 
      normal diet had decreased levels of colonic H2S synthesis, a 40% increase in 
      serum homocysteine, and a phenotype similar to wild-type mice with Hhcy. 
      IL-10-deficient mice fed the vitamin B-deficient diet exhibited more severe 
      colonic inflammation, but the normal elevation of colonic H2S synthesis was 
      absent. Administration of IL-10 to the IL-10-deficient mice restored colonic H2S 
      synthesis and significantly decreased serum homocysteine levels. These results 
      suggest that the exacerbation of colitis in Hhcy is due in part to impaired 
      colonic H2S synthesis. Moreover, IL-10 plays a novel role in promoting H2S 
      production and homocysteine metabolism, which may have therapeutic value in 
      conditions characterized by Hhcy.
FAU - Flannigan, Kyle L
AU  - Flannigan KL
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
FAU - Agbor, Terence A
AU  - Agbor TA
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
FAU - Blackler, Rory W
AU  - Blackler RW
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
FAU - Kim, Janice J
AU  - Kim JJ
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
FAU - Khan, Waliul I
AU  - Khan WI
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
FAU - Verdu, Elena F
AU  - Verdu EF
AD  - Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
FAU - Ferraz, Jose G P
AU  - Ferraz JG
AD  - Departments of Medicine and.
FAU - Wallace, John L
AU  - Wallace JL
AD  - Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1; 
      and Department of Pharmacology and Toxicology, University of Toronto, Toronto, 
      ON, Canada M5S 1A8 altapharm@hotmail.com.
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140903
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Recombinant Proteins)
RN  - 130068-27-8 (Interleukin-10)
RN  - 9042-14-2 (Dextran Sulfate)
RN  - EC 1.11.1.7 (Peroxidase)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
RN  - Homocysteinemia
SB  - IM
MH  - Animals
MH  - Colitis/chemically induced/*complications/pathology
MH  - Colon/metabolism/pathology
MH  - Dextran Sulfate
MH  - Diet
MH  - *Disease Progression
MH  - Humans
MH  - Hydrogen Sulfide/*metabolism
MH  - Hyperhomocysteinemia/*complications/*metabolism/pathology
MH  - Interleukin-10/deficiency/*metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Peroxidase/metabolism
MH  - Rats, Wistar
MH  - Recombinant Proteins/administration & dosage/pharmacology
MH  - *Signal Transduction
PMC - PMC4169975
COIS- The authors declare no conflict of interest.
EDAT- 2014/09/05 06:00
MHDA- 2015/04/24 06:00
PMCR- 2014/09/03
CRDT- 2014/09/05 06:00
PHST- 2014/09/05 06:00 [entrez]
PHST- 2014/09/05 06:00 [pubmed]
PHST- 2015/04/24 06:00 [medline]
PHST- 2014/09/03 00:00 [pmc-release]
AID - 1413390111 [pii]
AID - 201413390 [pii]
AID - 10.1073/pnas.1413390111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13559-64. doi: 
      10.1073/pnas.1413390111. Epub 2014 Sep 3.