PMID- 21972293
OWN - NLM
STAT- MEDLINE
DCOM- 20120116
LR  - 20211020
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 118
IP  - 20
DP  - 2011 Nov 17
TI  - Positive feedback between PGE2 and COX2 redirects the differentiation of human 
      dendritic cells toward stable myeloid-derived suppressor cells.
PG  - 5498-505
LID - 10.1182/blood-2011-07-365825 [doi]
AB  - Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing 
      roles in the immune system. In the present study, we report that the 
      establishment of a positive feedback loop between prostaglandin E(2) (PGE(2)) and 
      cyclooxygenase 2 (COX2), the key regulator of PGE(2) synthesis, represents the 
      determining factor in redirecting the development of CD1a(+) DCs to 
      CD14(+)CD33(+)CD34(+) monocytic MDSCs. Exogenous PGE(2) and such diverse COX2 
      activators as lipopolysaccharide, IL-1beta, and IFNgamma all induce monocyte expression 
      of COX2, blocking their differentiation into CD1a(+) DCs and inducing endogenous 
      PGE(2), IDO1, IL-4Ralpha, NOS2, and IL-10, typical MDSC-associated suppressive 
      factors. The addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is 
      sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte 
      (CTL)-suppressive function. In accordance with the key role of PGE(2) in the 
      physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in 
      ovarian cancer are closely correlated with local PGE(2) production, whereas the 
      cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of 
      COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses 
      the production of MDSC-associated suppressive factors and the CTL-inhibitory 
      function of fully developed MDSCs from cancer patients. The central role of 
      COX2-PGE(2) feedback in the induction and persistence of MDSCs highlights the 
      potential for its manipulation to enhance or suppress immune responses in cancer, 
      autoimmunity, or transplantation.
FAU - Obermajer, Natasa
AU  - Obermajer N
AD  - Department of Surgery, University of Pittsburgh,Hillman Cancer Center, UPCI 
      Research Pavilion, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.
FAU - Muthuswamy, Ravikumar
AU  - Muthuswamy R
FAU - Lesnock, Jamie
AU  - Lesnock J
FAU - Edwards, Robert P
AU  - Edwards RP
FAU - Kalinski, Pawel
AU  - Kalinski P
LA  - eng
GR  - P01 CA132714/CA/NCI NIH HHS/United States
GR  - 1P01 CA132714/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111004
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, CD34)
RN  - 0 (Antigens, Differentiation, Myelomonocytic)
RN  - 0 (CD33 protein, human)
RN  - 0 (Lipopolysaccharide Receptors)
RN  - 0 (PTGER2 protein, human)
RN  - 0 (Receptors, Prostaglandin E, EP2 Subtype)
RN  - 0 (Receptors, Prostaglandin E, EP4 Subtype)
RN  - 0 (Sialic Acid Binding Ig-like Lectin 3)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.14.99.1 (PTGS2 protein, human)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Antigens, CD/metabolism
MH  - Antigens, CD34/metabolism
MH  - Antigens, Differentiation, Myelomonocytic/metabolism
MH  - Ascites/immunology
MH  - CD8-Positive T-Lymphocytes/cytology/immunology
MH  - Cell Differentiation/immunology
MH  - Cyclooxygenase 2/*metabolism
MH  - Dendritic Cells/cytology/*immunology/metabolism
MH  - Dinoprostone/*metabolism
MH  - Feedback, Physiological/physiology
MH  - Female
MH  - Humans
MH  - Immunotherapy/methods
MH  - Lipopolysaccharide Receptors/metabolism
MH  - Myeloid Cells/cytology/*immunology/metabolism
MH  - Ovarian Neoplasms/*immunology/therapy
MH  - Receptors, Prostaglandin E, EP2 Subtype/metabolism
MH  - Receptors, Prostaglandin E, EP4 Subtype/metabolism
MH  - Sialic Acid Binding Ig-like Lectin 3
MH  - T-Lymphocytes, Cytotoxic/cytology/immunology
PMC - PMC3217352
EDAT- 2011/10/06 06:00
MHDA- 2012/01/17 06:00
PMCR- 2012/11/17
CRDT- 2011/10/06 06:00
PHST- 2011/10/06 06:00 [entrez]
PHST- 2011/10/06 06:00 [pubmed]
PHST- 2012/01/17 06:00 [medline]
PHST- 2012/11/17 00:00 [pmc-release]
AID - S0006-4971(20)40327-1 [pii]
AID - 2011/365825 [pii]
AID - 10.1182/blood-2011-07-365825 [doi]
PST - ppublish
SO  - Blood. 2011 Nov 17;118(20):5498-505. doi: 10.1182/blood-2011-07-365825. Epub 2011 
      Oct 4.