PMID- 30544623
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200225
IS  - 2073-4409 (Print)
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 7
IP  - 12
DP  - 2018 Dec 7
TI  - Role of the p38 MAPK/C/EBPbeta Pathway in the Regulation of Phenotype and IL-10 and 
      IL-12 Production by Tolerogenic Bone Marrow-Derived Dendritic Cells.
LID - 10.3390/cells7120256 [doi]
LID - 256
AB  - Dendritic cells (DCs) play a major role in innate and adaptive immunity and 
      self-immune tolerance. Immunogenic versus tolerogenic DC functions are dictated 
      by their levels of costimulatory molecules and their cytokine expression profile. 
      The transcription factor C/EBPbeta regulates the expression of several inflammatory 
      genes in many cell types including macrophages. However, little is known 
      regarding the role of C/EBPbeta in tolerogenic versus immunogenic DCs functions. We 
      have previously reported that bone marrow-derived DCs generated with GM-CSF 
      (GM/DCs) acquire the signature of semi-mature tolerogenic IL-10-producing DCs as 
      opposed to immunogenic DCs generated with GM-CSF and IL-4 (IL-4/DCs). Here, we 
      show that tolerogenic GM/DCs exhibit higher levels of phosphorylation and 
      enhanced DNA binding activity of C/EBPbeta and CREB than immunogenic IL-4/DCs. We 
      also show that the p38 MAPK/CREB axis and GSK3 play an important role in 
      regulating C/EBPbeta phosphorylation and DNA binding activity. Inhibition of p38 
      MAPK in GM/DCs resulted in a drastic decrease of C/EBPbeta and CREB DNA binding 
      activities, a reduction of their IL-10 production and an increase of their 
      IL-12p70 production, a characteristic of immunogenic IL-4/DCs. We also present 
      evidence that GSK3 inhibition in GM/DCs reduced C/EBPbeta DNA binding activity and 
      increased expression of costimulatory molecules in GM/DCs and their production of 
      IL-10. Analysis of GM/DCs of C/EBPbeta(-/-) mice showed that C/EBPbeta was essential to 
      maintain the semimature phenotype and the production of IL-10 as well as low CD4(+) 
      T cell proliferation. Our results highlight the importance of the p38MAPK-C/EBPbeta 
      pathway in regulating phenotype and function of tolerogenic GM/DCs.
FAU - Guindi, Chantal
AU  - Guindi C
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. chantal.guindi@usherbrooke.ca.
FAU - Cloutier, Alexandre
AU  - Cloutier A
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. alexander.cloutier@usherbrooke.ca.
FAU - Gaudreau, Simon
AU  - Gaudreau S
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. sgaudreau@ibiosolutions.com.
FAU - Zerif, Echarki
AU  - Zerif E
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. echarki.zerif@usherbrooke.ca.
FAU - McDonald, Patrick P
AU  - McDonald PP
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. patrick.mcdonald@usherbrooke.ca.
FAU - Tatsiy, Olga
AU  - Tatsiy O
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. olga.tatsiy@usherbrooke.ca.
FAU - Asselin, Claude
AU  - Asselin C
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. claude.asselin@usherbrooke.ca.
FAU - Dupuis, Gilles
AU  - Dupuis G
AUID- ORCID: 0000-0003-4216-5201
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. gilles.dupuis@usherbrooke.ca.
FAU - Gris, Denis
AU  - Gris D
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. denis.gris@usherbooke.ca.
FAU - Amrani, And Abdelaziz
AU  - Amrani AA
AD  - Immunology Division, Faculty of Medicine and Health Sciences and Centre de 
      Recherche du CHUS, 3001, 12th Avenue North, Universite de Sherbrooke, Sherbrooke, 
      QC J1H 5N4, Canada. abdelaziz.amrani@usherbrooke.ca.
LA  - eng
GR  - MOP-300762/Canadian Institutes of Health Research/Canada
GR  - RGPIN-2015-03671/Natural Sciences and Engineering Research Council of Canada/
PT  - Journal Article
DEP - 20181207
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
PMC - PMC6316502
OTO - NOTNLM
OT  - CCAAT/enhancer-binding protein beta (C/EBPbeta)
OT  - IL-12)
OT  - Interleukins 10 and 12 (IL-10
OT  - tolerogenic bone marrow-derived dendritic cells (BMDCs)
COIS- The authors declare no conflict of interest.
EDAT- 2018/12/14 06:00
MHDA- 2018/12/14 06:01
PMCR- 2018/12/01
CRDT- 2018/12/15 06:00
PHST- 2018/09/08 00:00 [received]
PHST- 2018/11/28 00:00 [revised]
PHST- 2018/12/04 00:00 [accepted]
PHST- 2018/12/15 06:00 [entrez]
PHST- 2018/12/14 06:00 [pubmed]
PHST- 2018/12/14 06:01 [medline]
PHST- 2018/12/01 00:00 [pmc-release]
AID - cells7120256 [pii]
AID - cells-07-00256 [pii]
AID - 10.3390/cells7120256 [doi]
PST - epublish
SO  - Cells. 2018 Dec 7;7(12):256. doi: 10.3390/cells7120256.