PMID- 21307853
OWN - NLM
STAT- MEDLINE
DCOM- 20110325
LR  - 20211020
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 471
IP  - 7337
DP  - 2011 Mar 10
TI  - Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to 
      dietary antigens.
PG  - 220-4
LID - 10.1038/nature09849 [doi]
AB  - Under physiological conditions the gut-associated lymphoid tissues not only 
      prevent the induction of a local inflammatory immune response, but also induce 
      systemic tolerance to fed antigens. A notable exception is coeliac disease, where 
      genetically susceptible individuals expressing human leukocyte antigen (HLA) 
      HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses 
      against dietary gluten, a protein present in wheat. The mechanisms underlying 
      this dysregulated mucosal immune response to a soluble antigen have not been 
      identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a 
      critical role in the induction of intestinal regulatory responses. Here we find 
      in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut 
      of coeliac disease patients, retinoic acid rapidly activates dendritic cells to 
      induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory 
      cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, 
      retinoic acid acted as an adjuvant that promoted rather than prevented 
      inflammatory cellular and humoral responses to fed antigen. Altogether, these 
      findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation 
      of tolerance to dietary antigens.
FAU - DePaolo, R W
AU  - DePaolo RW
AD  - Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
FAU - Abadie, V
AU  - Abadie V
FAU - Tang, F
AU  - Tang F
FAU - Fehlner-Peach, H
AU  - Fehlner-Peach H
FAU - Hall, J A
AU  - Hall JA
FAU - Wang, W
AU  - Wang W
FAU - Marietta, E V
AU  - Marietta EV
FAU - Kasarda, D D
AU  - Kasarda DD
FAU - Waldmann, T A
AU  - Waldmann TA
FAU - Murray, J A
AU  - Murray JA
FAU - Semrad, C
AU  - Semrad C
FAU - Kupfer, S S
AU  - Kupfer SS
FAU - Belkaid, Y
AU  - Belkaid Y
FAU - Guandalini, S
AU  - Guandalini S
FAU - Jabri, B
AU  - Jabri B
LA  - eng
GR  - R01DK71003/DK/NIDDK NIH HHS/United States
GR  - R01 DK067180-07/DK/NIDDK NIH HHS/United States
GR  - P30 DK042086-19/DK/NIDDK NIH HHS/United States
GR  - DK42086/DK/NIDDK NIH HHS/United States
GR  - R56 DK071003/DK/NIDDK NIH HHS/United States
GR  - K08 CA142892/CA/NCI NIH HHS/United States
GR  - R56 DK071003-05/DK/NIDDK NIH HHS/United States
GR  - R01 DK67180/DK/NIDDK NIH HHS/United States
GR  - R01 DK067180-06/DK/NIDDK NIH HHS/United States
GR  - R01 DK067180/DK/NIDDK NIH HHS/United States
GR  - P30 DK042086/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 - 20110209
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DQ8 antigen)
RN  - 0 (Interleukin-15)
RN  - 0 (Interleukin-23)
RN  - 0 (Receptors, Interleukin-12)
RN  - 187348-17-0 (Interleukin-12)
RN  - 5688UTC01R (Tretinoin)
RN  - 8002-80-0 (Glutens)
RN  - 9007-90-3 (Gliadin)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
SB  - IM
CIN - Nature. 2011 Mar 10;471(7337):169-70. PMID: 21390118
CIN - Nat Rev Immunol. 2011 Mar;11(3):156. PMID: 21452586
CIN - Nat Rev Gastroenterol Hepatol. 2011 Apr;8(4):181. PMID: 21595057
CIN - Expert Rev Gastroenterol Hepatol. 2011 Jun;5(3):315-7. PMID: 21651349
MH  - Adjuvants, Immunologic/*pharmacology
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Animals
MH  - Celiac Disease/chemically induced/etiology/*immunology
MH  - Cells, Cultured
MH  - Child
MH  - Child, Preschool
MH  - Coculture Techniques
MH  - Dendritic Cells/drug effects/enzymology/immunology/metabolism
MH  - Diet
MH  - Forkhead Transcription Factors/metabolism
MH  - Gliadin/administration & dosage/immunology
MH  - Glutens/administration & dosage/*immunology
MH  - HLA-DQ Antigens/genetics/immunology
MH  - Humans
MH  - Immune Tolerance/drug effects
MH  - Inflammation/immunology
MH  - Interleukin-12/biosynthesis/immunology/metabolism
MH  - Interleukin-15/genetics/*immunology
MH  - Interleukin-23/immunology/metabolism
MH  - Intestinal Mucosa/cytology/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinase 8/metabolism
MH  - Phosphorylation/drug effects
MH  - Receptors, Interleukin-12/deficiency
MH  - T-Lymphocytes, Regulatory/cytology/drug effects/immunology/metabolism
MH  - Tretinoin/immunology/*pharmacology
MH  - Young Adult
PMC - PMC3076739
MID - NIHMS285468
EDAT- 2011/02/11 06:00
MHDA- 2011/03/26 06:00
PMCR- 2012/03/10
CRDT- 2011/02/11 06:00
PHST- 2010/03/25 00:00 [received]
PHST- 2011/01/19 00:00 [accepted]
PHST- 2011/02/11 06:00 [entrez]
PHST- 2011/02/11 06:00 [pubmed]
PHST- 2011/03/26 06:00 [medline]
PHST- 2012/03/10 00:00 [pmc-release]
AID - nature09849 [pii]
AID - 10.1038/nature09849 [doi]
PST - ppublish
SO  - Nature. 2011 Mar 10;471(7337):220-4. doi: 10.1038/nature09849. Epub 2011 Feb 9.