NSU-MD Faculty Articles
Pivotal Advance: Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE₂ catabolism in myeloid cells.
Publication Title
Journal of leukocyte biology
Publisher
John Wiley & Sons Ltd.
ISSN
0741-5400
Publication Date
11-1-2010
Keywords
Animals, Arginase, Bone Marrow Cells, Colonic Neoplasms, Cytokines, Dinoprostone, Female, Flow Cytometry, Immunosuppression, Macrophages, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Myeloid Cells, Phosphorylation, STAT1 Transcription Factor, STAT3 Transcription Factor, T-Lymphocytes
Abstract
Recent studies suggest that tumor-infiltrated myeloid cells frequently up-regulate COX-2 expression and have enhanced PGE₂ metabolism. This may affect the maturation and immune function of tumor-infiltrated antigen-presenting cells. In vitro studies demonstrate that tumor-derived factors can skew GM-CSF-driven differentiation of T(h)1-oriented myeloid APCs into M2-oriented Ly6C(+)F4/80(+) MDSCs or Ly6C(-)F4/80(+) arginase-expressing macrophages. These changes enable myeloid cells to produce substantial amounts of IL-10, VEGF, and MIP-2. The tumor-mediated inhibition of APC differentiation was associated with the up-regulated expression of PGE₂-forming enzymes COX-2, mPGES1 in myeloid cells, and the simultaneous repression of PGE(2)-catabolizing enzyme 15-PGDH. The presence of tumor-derived factors also led to a reduced expression of PGT but promoted the up-regulation of MRP4, which works as a PGE₂ efflux receptor. Addition of COX-2 inhibitor to the BM cell cultures could prevent the tumor-induced skewing of myeloid cell differentiation, partially restoring cell phenotype and down-regulating the arginase expression in the myeloid APCs. Our study suggests that tumors impair the intracellular PGE(2) catabolism in myeloid cells through simultaneous stimulation of PGE(2)-forming enzymes and inhibition of PGE₂-degrading systems. This tumor-induced dichotomy drives the development of M2-oriented, arginase-expressing macrophages or the MDSC, which can be seen frequently among tumor-infiltrated myeloid cells.
DOI
10.1189/jlb.1209821
Volume
88
Issue
5
First Page
839
Last Page
848
Disciplines
Medicine and Health Sciences
NSUWorks Citation
Eruslanov, Evgeniy; Daurkin, Irina; Ortiz, Javier; Vieweg, Johannes; and Kusmartsev, Sergei, "Pivotal Advance: Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE₂ catabolism in myeloid cells." (2010). NSU-MD Faculty Articles. 55.
https://nsuworks.nova.edu/hpd_md_facarticles/55
