Inflammation restraining effects of prostaglandin E2 on natural killer–dendritic cell (NK-DC) interaction are imprinted during DC maturation

Abstract

Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance . In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer-dendritic cell (NK-DC) crosstalk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-␥/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation. As a consequence, these DCs fail to attract NK cells and show a decreased capacity to trigger NK cell IFN-␥ production, which in turn leads to reduced T-helper 1 polarization. In addition, the presence of PGE2 during DC maturation impairs DC-mediated augmentation of NK-cell cytotoxicity. Op- IntroductionProstaglandins (PGs) are potent immune modulators that are produced during inflammation after the conversion of arachidonic acid by cyclooxygenase (COX). 1 Furthermore, PGs are also abundantly produced by various types of tumors. 2 COX2 expression, which is correlated with a poor prognosis, is induced in a variety of human premalignant and malignant tumors, including solid tumors as well as hematologic malignancies. [3][4][5][6] Several lines of evidence demonstrate that COX2-derived PGs are involved in the promotion of tumor growth by regulation of cancer cell proliferation, apoptosis, migration, and invasion. [7][8][9][10][11] PGs are also produced by tumor-surrounding cells, creating a tumor-supporting environment by enhancing angiogenesis and inhibiting tumor immune surveillance. 2,[11][12][13][14] Of all prostaglandins, PGE2 has a pivotal role in tumor immunosuppression. It has been hypothesized that this effect is caused by induction of a permanent state of inflammation, 2 resulting in phenotypic and functional changes of T-helper (T H ) cells, cytotoxic T-lymphocyte (CTL) cells, dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells. 12 PGE2 has been shown to deviate T H cell skewing from an antitumor T H 1 response toward a T H 2/T H 17 response by direct binding to these cells. [15][16][17] In addition, PGE2 is responsible for shifting the balance of IL-12/IL-23 production by DCs toward IL-23, which is a very potent cytokine responsible for T H 17 expansion and survival. 18,19 As a consequence, less IL-12 and other proinflammatory cytokines are produced, thereby inhibiting T H 1 polarization. 17,20 PGE2 also decreases the cytotoxic capacity of CTLs directly by inducing the expression of inhibitory receptors on CTLs 21 and indirectly by inhibiting DC maturation and antigen presentation. 22,23 Moreover, tumor-associated PGE2 has been reported to be responsible for the preferential attraction and induction of regulatory T cells, creating an immune-regulatory microenvironment. 24,25 Next to the modulating effects of PGE2 on the effector mech...

Secretion of immunoregulatory cytokines by mesenchymal stem cells

“…Acting by a contact or paracrine manner [229,231] , PGE2 has a systemic antiinflammatory effect of reducing TNFα, IL-6 and vascular permeability in an experimental model of sepsis [230] . Particularly, the cellular targets of PGE2 are PBMCs, NK cells, monocytes, macrophages and the transitional processes of differentiation of monocytes into immature DCs [228,230,232] . PGE2 indirectly affects polyclonally or allogenically activated PBMCs by substantial suppression of proliferation and IFNγ secretion [227,229,231] .…”

“…They are subjected to the direct effect of PGE2, resulting in reduced effectiveness of reaching the stage of immature DCs from monocytes showing an affected phenotype as a low number of CD1a cells and decreased expression of co-stimulatory CD80, CD86 [228] and antigen-presenting molecules MHC Ⅱ [231] . Furthermore, when co-cultured with MSCs, the production of IL-12 from APCs (especially DCs) is low [228,231,232] , while IL-10 (from DCs and macrophages) is increased [227,230] . In total, when differentiating in the presence of MSCs, DCs stay immature in a tolerogenic state and unable to elicit a Th1 immune response.…”

“…Retained in an undifferentiated state, DCs when in co-culture with MSCs largely deteriorate/aggravate the cytotoxicity properties of NK cells as well. Investigations show that due to changed chemokine profile and reduced IL-12 secretion from DCs, NK cells do not properly recruit to DCs [232] . Under these circumstances, NK cells have low activation, diminished IFNγ secretion and cytotoxicity against their targets [232] , including the reactivity against MSCs [234] .…”

“…Investigations show that due to changed chemokine profile and reduced IL-12 secretion from DCs, NK cells do not properly recruit to DCs [232] . Under these circumstances, NK cells have low activation, diminished IFNγ secretion and cytotoxicity against their targets [232] , including the reactivity against MSCs [234] . Summarizing the influence of PGE2 on immune cells with regulatory function endows MSCs a central place in controlling of inflammatory responses.…”

Prostaglandin E2 Potentiates Mesenchymal Stem Cell–Induced IL-10+IFN-γ+CD4+ Regulatory T Cells To Control Transplant Arteriosclerosis

“…Misoprostol, a synthetic analog of PGE 1 , binds to and activates each of the four heptahelical G protein-coupled E prostanoid receptors normally ligated by the endogenous PGE 2 (43). The regulatory effects of misoprostol on both innate and adaptive immune systems were proved to be similar to those of natural PGE 2 (44,45) . Misoprostol, given in the dosage used in this study (200 mg, 4 times daily) and in the presence of conventional immunosuppressants, was reported to reduce acute rejection in renal allografts (46).…”