Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources

Najar, Mehdi; Raicevic, Gordana; Boufker, Hicham Id; Fayyad‐Kazan, Hussein; Bruyn, Cécile De; Meuleman, Nathalie; Bron, Dominique; Toungouz, Michel; Lagneaux, Laurence

doi:10.1016/j.cellimm.2010.06.006

Cited by 254 publications

(217 citation statements)

References 44 publications

Supporting

Mentioning

199

Contrasting

Unclassified

Order By: Relevance

“…COX-2 is a key enzyme in the synthesis of PGE2, and MSC-derived PGE2 is involved in skewing the inflammatory environment towards an anti-inflammatory profile, altering the cytokine secretion profile of T-cell subsets (Th1, Th2, or Tregs). 27,33 IL-8 is known as a specific neutrophil-attracting chemokine, and activated MSCs can mediate neutrophil recruitment through IL-8. 34 IL-6 could promote MSC secretion of PGE2 35 as well as maintain the proliferative and undifferentiated state of bone marrowderived MSCs.…”

Section: Discussionmentioning

confidence: 99%

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

et al. 2012

View full text Add to dashboard Cite

Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1b (IL-1b) is one of the most important inflammatory mediators, growing evidence indicates that IL-1b signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1b signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1b-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1b-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1b-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1b-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1b-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.

show abstract

Section: Discussionmentioning

confidence: 99%

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

et al. 2012

View full text Add to dashboard Cite

show abstract

“…21 Moreover, bone marrow-derived mesenchymal stromal cells have been reported to suppress T-cell proliferation by the action of PGE 2 . 22 Finally, most reports claim that PGE 2 skews the immune response towards a T h 2 response, although conflicting results have been reported. 16,23,24 Notably, the alleged Tcell stimulatory effect of PGE 2 has only been shown for CD4 1 T h 1 cells in vivo and in models of autoimmunity.…”

Section: Short Reportmentioning

confidence: 99%

Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

Eberstål

Sandén

Fritzell

et al. 2013

Intl Journal of Cancer

View full text Add to dashboard Cite

Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E 2 (PGE 2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE 2 and COX-2 have been shown in several tumor types, including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 mg/kg/day; 63% cure rate). Both combined therapies induced a systemic antitumor response of proliferating CD4 1 and CD8 1 T cells, and further analysis revealed T helper 1 (T h 1) cell supremacy. The GL261 tumor cell line produced low levels of PGE 2 in vitro, and co-staining at the tumor site demonstrated that a large fraction of the COX-2 1 cells were derived from CD45 1 immune cells and more specifically macrophages (F4/80 1 ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE 2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target.The prognosis for patients with high-grade brain tumors remains poor despite extensive treatment, including surgery, radiotherapy and chemotherapy. 1,2 Treatment failure is mainly ascribed to the infiltrative capacity of the tumor cells, which form tumor microsatellites deep in the normal brain parenchyma. Immunotherapy represents a novel approach that could target these residual tumor cells and has been shown to be safe and induce prolonged survival in clinical trials. [3][4][5] However, the therapeutic effect of immunotherapy is often down-regulated because of immunosuppression.Prostaglandin E 2 (PGE 2 ) constitutes a key suppressive mediator and is synthesized from arachidonic acid by cyclooxygenases (COX) and prostaglandin synthases. The inducible COX-2 and the downstream microsomal prostaglandin E synthase-1 (mPGES-1) are overexpressed in a wide range of tumors, including high-grade brain tumors, and most reports show correlations with poor prognosis, although adverse results are reported. 6-8 PGE 2 has been alleged to exert immunosuppression by either direct effects on T cells by stimulating T h 2 cytokines as interleukin-10 (IL-10) and simultaneously inhibiting T h 1 cytokines as interferon-g (IFN-g) or by indirect effects via promotion of myeloid-derived suppressor cells (MDSCs) and regulatory T (T reg ) cells, which in turn induce T cell tolerance. [9][10][11][12] We and others have shown that peripheral immunotherapy using granulocyte macrophage-colony stimu...

show abstract

“…However, when T cells are already stimulated, MSCs reduce the expression levels of their activation markers. Some studies have shown that high doses of MSCs possess immunosuppressive activity whereas low dose MSC therapy could be immunostimulatory [27,28] or fail to inhibit lymphocyte proliferation [29,30]. One study directly assessed MSC dose in a canine disc degeneration model and found that MSCs were least viable after injection at a low dose (10 5 ), that there were more apoptotic cells at the high dose of…”

Section: Msc Dosementioning

confidence: 99%

“…MSCs secrete soluble mediators and directly interact with T-cells to modulate their activity [29,36,37]. MSCs can induce apoptosis of activated T cells, induce cell cycle arrest, decrease T-cell proliferation [30,38] and alter T cell phenotype. MSCs target T-cell subsets (CD4+, CD8+, CD2+ and CD3+ subpopulations) equally [30].…”

Section: T Lymphocytesmentioning

confidence: 99%

“…MSCs can induce apoptosis of activated T cells, induce cell cycle arrest, decrease T-cell proliferation [30,38] and alter T cell phenotype. MSCs target T-cell subsets (CD4+, CD8+, CD2+ and CD3+ subpopulations) equally [30]. MSCs in direct contact with lymphocytes may inhibit lymphocyte apoptosis via the secretion of IL-6 or nitric oxide (NO) [35][36][37].…”

Section: T Lymphocytesmentioning

confidence: 99%

See 1 more Smart Citation

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

Borjesson

Peroni

2011

Clinics in Laboratory Medicine

View full text Add to dashboard Cite

Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources

Cited by 254 publications

References 44 publications

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

Contact Info

Product

Resources

About