PMID- 31355296
OWN - NLM
STAT- MEDLINE
DCOM- 20191220
LR  - 20200225
IS  - 2314-7156 (Electronic)
IS  - 2314-8861 (Print)
IS  - 2314-7156 (Linking)
VI  - 2019
DP  - 2019
TI  - STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic 
      Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced 
      Arthritis.
PG  - 1982570
LID - 10.1155/2019/1982570 [doi]
LID - 1982570
AB  - Dendritic cells (DCs) have the ability to induce tolerance or inflammation in 
      response to self-antigens, which makes them fundamental players in autoimmunity. 
      In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition 
      of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4(+) 
      T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 
      and TGF-beta, inducing the generation of CD4(+) T-cells with suppressive activity 
      (Treg), which promote tolerance to self-constituents. Previous studies have shown 
      that STAT3 signalling in DCs attenuates the production of proinflammatory 
      cytokines, whilst NF-kappaB activation promotes it. In this study, we aimed to 
      generate DCs displaying strong and constitutive tolerogenic profile to be used as 
      immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs 
      with lentiviral particles codifying for a constitutively active version of STAT3 
      (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-kappaB 
      (IkappaBalpha superrepressor (IkappaBalphaSR)), and their therapeutic potential was evaluated in 
      a mouse model of arthritis induced by collagen (CIA). Our results show that 
      STAT3ca transduction favoured the production of the anti-inflammatory mediator 
      IL-10, whereas IkappaBalphaSR transduction attenuated the expression of the 
      proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and 
      IkappaBalphaSR-transduced DCs separately exerted a mild but significant therapeutic 
      effect reducing the severity of CIA development. Furthermore, when DCs were 
      transduced with both STAT3ca and IkappaBalphaSR together, they reduced CIA manifestation 
      significantly stronger than when transduced with only STAT3ca or IkappaBalphaSR 
      separately. These results show STAT3 and NF-kappaB as two important and complementary 
      regulators of the tolerogenic behaviour of DCs, which should be considered as 
      molecular targets in the design of DC-based suppressive immunotherapies for the 
      treatment of autoimmune disorders.
FAU - Prado, Carolina
AU  - Prado C
AD  - Laboratorio de Neuroinmunologia, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
FAU - Ugalde, Valentina
AU  - Ugalde V
AD  - Laboratorio de Neuroinmunologia, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
FAU - Gonzalez, Hugo
AU  - Gonzalez H
AD  - Laboratorio de Neuroinmunologia, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
FAU - Figueroa, Alicia
AU  - Figueroa A
AD  - Laboratorio de Neuroinmunologia, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
FAU - Lopez, Ernesto
AU  - Lopez E
AD  - Laboratorio de Inmunoterapia Genica, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
FAU - Lladser, Alvaro
AU  - Lladser A
AD  - Laboratorio de Inmunoterapia Genica, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
FAU - Pacheco, Rodrigo
AU  - Pacheco R
AUID- ORCID: 0000-0001-8057-9806
AD  - Laboratorio de Neuroinmunologia, Fundacion Ciencia & Vida, Santiago 7780272, 
      Chile.
AD  - Departamento de Ciencias Biologicas, Facultad de Ciencias de la Vida, Universidad 
      Andres Bello, Santiago 8370146, Chile.
LA  - eng
PT  - Journal Article
DEP - 20190701
PL  - Egypt
TA  - J Immunol Res
JT  - Journal of immunology research
JID - 101627166
RN  - 0 (NF-kappa B)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 130068-27-8 (Interleukin-10)
RN  - 187348-17-0 (Interleukin-12)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/immunology/metabolism/*therapy
MH  - Autoimmunity
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Dendritic Cells/immunology/metabolism/*transplantation
MH  - Humans
MH  - Immune Tolerance/*immunology
MH  - Inflammation
MH  - Interleukin-10/metabolism
MH  - Interleukin-12/metabolism
MH  - Male
MH  - Mice
MH  - NF-kappa B/*antagonists & inhibitors
MH  - STAT3 Transcription Factor/*genetics/metabolism
MH  - Th1 Cells/immunology
MH  - Th17 Cells/immunology
PMC - PMC6636450
EDAT- 2019/07/30 06:00
MHDA- 2019/12/21 06:00
PMCR- 2019/07/01
CRDT- 2019/07/30 06:00
PHST- 2019/02/06 00:00 [received]
PHST- 2019/04/02 00:00 [revised]
PHST- 2019/06/10 00:00 [accepted]
PHST- 2019/07/30 06:00 [entrez]
PHST- 2019/07/30 06:00 [pubmed]
PHST- 2019/12/21 06:00 [medline]
PHST- 2019/07/01 00:00 [pmc-release]
AID - 10.1155/2019/1982570 [doi]
PST - epublish
SO  - J Immunol Res. 2019 Jul 1;2019:1982570. doi: 10.1155/2019/1982570. eCollection 
      2019.