PMID- 22479554
OWN - NLM
STAT- MEDLINE
DCOM- 20121105
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 3
DP  - 2012
TI  - A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine 
      expression and ameliorates experimental colitis.
PG  - e34172
LID - 10.1371/journal.pone.0034172 [doi]
LID - e34172
AB  - Nuclear factor of activated T cells (NFAT) plays a critical role in the 
      development and function of immune and non-immune cells. Although NFAT is a 
      central transcriptional regulator of T cell cytokines, its role in macrophage 
      specific gene expression is less defined. Previous work from our group 
      demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we 
      further investigate NFAT function in murine macrophages and determined the 
      effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental 
      colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with 
      tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-gamma induced 
      IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also 
      decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was 
      reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10(-/-)) 
      mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent 
      of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was 
      administered systemically to Il10(-/-) mice with piroxicam-induced colitis. 
      11R-VIVIT treated mice demonstrated significant improvement in colitis compared 
      to mice treated with an inactive peptide. Moreover, decreased spontaneous 
      secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was 
      demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, 
      also regulates important innate inflammatory pathways in macrophages. Selective 
      blocking of NFAT via a cell permeable inhibitory peptide is a promising 
      therapeutic strategy for the treatment of inflammatory bowel diseases.
FAU - Elloumi, Houda Z
AU  - Elloumi HZ
AD  - Center for Gastrointestinal Biology and Diseases, Department of Medicine, 
      University of North Carolina School of Medicine, Chapel Hill, North Carolina, 
      United States of America.
FAU - Maharshak, Nitsan
AU  - Maharshak N
FAU - Rao, Kavitha N
AU  - Rao KN
FAU - Kobayashi, Taku
AU  - Kobayashi T
FAU - Ryu, Hyungjin S
AU  - Ryu HS
FAU - Muhlbauer, Marcus
AU  - Muhlbauer M
FAU - Li, Fengling
AU  - Li F
FAU - Jobin, Christian
AU  - Jobin C
FAU - Plevy, Scott E
AU  - Plevy SE
LA  - eng
GR  - R01 DK054452/DK/NIDDK NIH HHS/United States
GR  - R01 DK54452/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 - 20120327
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-12 Subunit p40)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (RNA, Messenger)
RN  - 130068-27-8 (Interleukin-10)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Bone Marrow Cells/cytology
MH  - Colitis/*metabolism/therapy
MH  - Cytokines/*biosynthesis
MH  - Disease Models, Animal
MH  - Green Fluorescent Proteins/metabolism
MH  - Inflammation
MH  - Interferon-gamma/metabolism
MH  - Interleukin-10/genetics
MH  - Interleukin-12 Subunit p40/metabolism
MH  - Lipopolysaccharides/metabolism
MH  - Macrophages/cytology/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microscopy, Fluorescence/methods
MH  - NFATC Transcription Factors/*antagonists & inhibitors/*metabolism
MH  - Nitric Oxide Synthase Type II/genetics
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/metabolism
MH  - Tacrolimus/pharmacology
PMC - PMC3313977
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/04/06 06:00
MHDA- 2012/11/06 06:00
PMCR- 2012/03/27
CRDT- 2012/04/06 06:00
PHST- 2011/12/12 00:00 [received]
PHST- 2012/02/28 00:00 [accepted]
PHST- 2012/04/06 06:00 [entrez]
PHST- 2012/04/06 06:00 [pubmed]
PHST- 2012/11/06 06:00 [medline]
PHST- 2012/03/27 00:00 [pmc-release]
AID - PONE-D-11-24821 [pii]
AID - 10.1371/journal.pone.0034172 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(3):e34172. doi: 10.1371/journal.pone.0034172. Epub 2012 Mar 27.