PMID- 22786766
OWN - NLM
STAT- MEDLINE
DCOM- 20121019
LR  - 20211021
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 189
IP  - 4
DP  - 2012 Aug 15
TI  - IL-10 regulates Il12b expression via histone deacetylation: implications for 
      intestinal macrophage homeostasis.
PG  - 1792-9
LID - 10.4049/jimmunol.1200042 [doi]
AB  - To prevent excessive inflammatory responses to commensal microbes, intestinal 
      macrophages, unlike their systemic counterparts, do not produce inflammatory 
      cytokines in response to enteric bacteria. Consequently, loss of macrophage 
      tolerance to the enteric microbiota plays a central role in the pathogenesis of 
      inflammatory bowel diseases. Therefore, we examined whether the hyporesponsive 
      phenotype of intestinal macrophages is programmed by prior exposure to the 
      microbiota. IL-10, but not in vivo exposure to the microbiota, programs 
      intestinal macrophage tolerance, because wild-type (WT) colonic macrophages from 
      germ-free and specific pathogen-free (SPF)-derived mice produce IL-10, but not 
      IL-12 p40, when activated with enteric bacteria. Basal and activated IL-10 
      expression is mediated through a MyD88-dependent pathway. Conversely, colonic 
      macrophages from germ-free and SPF-derived colitis-prone Il10(-/-) mice 
      demonstrated robust production of IL-12 p40. Next, mechanisms through which IL-10 
      inhibits Il12b expression were investigated. Although Il12b mRNA was transiently 
      induced in LPS-activated WT bone marrow-derived macrophages (BMDMs), expression 
      persisted in Il10(-/-) BMDMs. There were no differences in nucleosome remodeling, 
      mRNA stability, NF-kappaB activation, or MAPK signaling to explain prolonged 
      transcription of Il12b in Il10(-/-) BMDMs. However, acetylated histone H4 
      transiently associated with the Il12b promoter in WT BMDMs, whereas association 
      of these factors was prolonged in Il10(-/-) BMDMs. Experiments using histone 
      deacetylase (HDAC) inhibitors and HDAC3 short hairpin RNA indicate that HDAC3 is 
      involved in histone deacetylation of the Il12b promoter by IL-10. These results 
      suggest that histone deacetylation on the Il12b promoter by HDAC3 mediates 
      homeostatic effects of IL-10 in macrophages.
FAU - Kobayashi, Taku
AU  - Kobayashi T
AD  - Department of Medicine, Center for Gastrointestinal Biology and Diseases, 
      University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
FAU - Matsuoka, Katsuyoshi
AU  - Matsuoka K
FAU - Sheikh, Shehzad Z
AU  - Sheikh SZ
FAU - Russo, Steven M
AU  - Russo SM
FAU - Mishima, Yoshiyuki
AU  - Mishima Y
FAU - Collins, Colm
AU  - Collins C
FAU - deZoeten, Edwin F
AU  - deZoeten EF
FAU - Karp, Christopher L
AU  - Karp CL
FAU - Ting, Jenny P Y
AU  - Ting JP
FAU - Sartor, R Balfour
AU  - Sartor RB
FAU - Plevy, Scott E
AU  - Plevy SE
LA  - eng
GR  - P30 DK034987/DK/NIDDK NIH HHS/United States
GR  - P40 RR018603/RR/NCRR NIH HHS/United States
GR  - R01 DK54452/DK/NIDDK NIH HHS/United States
GR  - T32 DK007737/DK/NIDDK NIH HHS/United States
GR  - R01 DK054452/DK/NIDDK NIH HHS/United States
GR  - F32 DK083186/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120711
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Histones)
RN  - 0 (IL10 protein, mouse)
RN  - 0 (Interleukin-12 Subunit p40)
RN  - 130068-27-8 (Interleukin-10)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - EC 3.5.1.98 (histone deacetylase 3)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - Gene Expression Regulation/*immunology
MH  - Histone Deacetylases/immunology/metabolism
MH  - Histones/genetics/immunology/metabolism
MH  - Homeostasis/*immunology
MH  - Immune Tolerance/genetics/immunology
MH  - Interleukin-10/*immunology
MH  - Interleukin-12 Subunit p40/*biosynthesis/genetics/immunology
MH  - Intestines/immunology/microbiology
MH  - Macrophages/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Promoter Regions, Genetic/genetics
PMC - PMC3411910
MID - NIHMS386413
EDAT- 2012/07/13 06:00
MHDA- 2012/10/20 06:00
PMCR- 2013/08/15
CRDT- 2012/07/13 06:00
PHST- 2012/07/13 06:00 [entrez]
PHST- 2012/07/13 06:00 [pubmed]
PHST- 2012/10/20 06:00 [medline]
PHST- 2013/08/15 00:00 [pmc-release]
AID - jimmunol.1200042 [pii]
AID - 10.4049/jimmunol.1200042 [doi]
PST - ppublish
SO  - J Immunol. 2012 Aug 15;189(4):1792-9. doi: 10.4049/jimmunol.1200042. Epub 2012 
      Jul 11.