High Levels Of Prostaglandin E2 Research Articles

Elevated prostaglandin E2 production by monocytes is responsible for the depressed levels of natural killer and lymphokine-activated killer cell function in patients with breast cancer

Human natural killer (NK) cells mediate spontaneous cytotoxicity against tumor cells and represent the main precursors of lymphokine-activated killer (LAK) cell activity. A comparison of some aspects of NK and LAK cell activity was undertaken in 85 preoperative patients with breast cancer and 75 healthy donors. NK cell activity (tested in 18-hour cultures of effector peripheral blood mononuclear cells [PBMC] with K562 or MOLT-4 tumor target cells) was significantly diminished in these patients as it was the fully mature LAK cell activity (i.e., interleukin-2 (IL-2)-induced cytotoxicity in PBMC) against NK resistant target cells. Using immunoenzymatic methods we showed that the reduced NK cell activity was due to abnormally high levels of prostaglandin E2 (PGE2) produced by monocytes in culture. PGE2 was found to suppress the production of IL-2 in these cultures. Removal of monocytes from PBMC restored to almost normal levels the deficient NK and LAK cell activity in patients with breast cancer and was also associated with a normalization in the levels of PGE2 and IL-2. Indomethacin and gamma-interferon (IFN-gamma) increased the NK and LAK cell activity in these patients up to the levels of healthy donors. When highly purified CD56+ cells (obtained by an immunomagnetic isolation technique) were used as effector cells, no differences in LAK cell activity could be noticed between healthy donors and patients with cancer. FACS and northern blot analyses demonstrated a PGE2-mediated down-regulation of IL-2 receptor (IL-2R) expression on CD56+ cells that correlated with reduced LAK cell activity. This inhibitory effect of PGE2 was noticeable in long-term LAK cultures and was abrogated in the presence of IFN-gamma or indomethacin. This study may have important implications in the potentiation of NK and LAK cell activity for immunotherapeutic protocols in patients with breast cancer.

PGE2and leucocyte levels in aqueous humor after lens extraction and intraocular lens implantation

In order to study the inflammatory response after cataract surgery and intraocular lens implantation the leukocyte (WBC) and prostaglandin E(2) (PGE(2)) levels in aqueous humor were measured in rabbit eyes at different time points (1, 3, 7, 14 and 28 days) postoperatively. In the first group lenses were implanted in the anterior chamber of the eye, without lens extraction, while in the second group the lens was removed and the IOL was placed in the capsular bag. A third group of animals was injected with 10 ng endotoxin into the vitreous in order to induce an inflammation of the uvea. In the endotoxin group high levels of WBC and PGE(2) were observed at 24 h postoperatively, followed by a decrease over time. In the intraocular lens groups WBC and PGE(2) were detected at all time points, and at higher levels compared to the endotoxin group. The WBC was high at day 1 and 3, declined over time, and then increased at day 28 postoperatively. The PGE(2) level was highest at day 3 in rabbits with anterior chamber lenses, while it peaked at day 7 in the animals with IOLs implanted in the capsular bag. In animals with the extracapsular lens extraction without an implanted IOL, the levels of WBC and PGE(2) decreased over time, and were statistically lower after one week compared with animals with an IOL placed in the capsular bag. The results demonstrate that the inflammatory response after cataract surgery persists for at least one month, probably due to surgical trauma and foreign body reactions. PGE(2) and WBC could be used to study postoperative trauma and biocompatibility of different IOL materials and designs.

Myelodysplastic syndrome (MDS)‐associated inhibitory activity on haemopoietic progenitor cells

We studied MDS-associated inhibitory activity, which inhibited colony formation in vitro of granulocyte-macrophage progenitors (CFU-GM). Macrophages obtained from MDS bone marrow mononuclear cells (BM-MNC) when pretreated with granulocyte-macrophage colony stimulating factor (GM-CSF) suppressed the growth of normal CFU-GM. These macrophages were designated as 'MDS-derived inhibitory macrophages'. Media conditioned by MDS-derived inhibitory macrophages (MDS-CM) also suppressed the growth of normal CFU-GM. In the MDS-CM, high levels of prostaglandin E2 (PGE2) and ferritin were found. However, MDS-CM did not contain detectable levels of tumour necrosis factor (TNF) or gamma-interferon (gamma-IFN). Antiserum against human placental ferritin and/or against PGE2 blocked the haemopoietic inhibitory activity to some extent. These results suggest that inhibitory macrophages may be responsible for the suppression of granulopoiesis in patients with MDS and that the suppression may be mediated by soluble factors including PGE2 and ferritin.

Possible role of prostaglandins in the regulation of mouse myoblasts

A differentiation-defective mouse myoblast subclone (DD-1), cells of which do not fuse into myotubes nor synthesize muscle-specific proteins, was employed to help define the role of eicosanoids in mouse myoblast differentiation. We observed by hplc, tlc, and radioimmunoassay that the DD-1 cells release strikingly higher levels of cyclooxygenase pathway products prostaglandin E2 and F2 alpha into the culture medium than the parental non-differentiation-defective cells (DZ). In contrast, the levels of 15-hydroxyeicosatetraenoic acid (15-HETE), a lipoxygenase product, and a putatively identified second lipoxygenase product (LLP) did not differ greatly in the two cell types. The DD-1 cells also have strikingly higher levels of cyclooxygenase activity than the parental cells as determined by intact and broken cell assays. Additional fusion-defective clones were isolated on the basis of their flattened appearance and ability to grow in "mitogen-poor" medium and these cells also released strikingly higher levels of prostaglandins E2 and F2 alpha into the growth medium. The "turn on" of the cyclooxygenase pathway in the DD-1 cells and other fusion-defective cells is consistent with the hypothesis that the products of this pathway contribute to the inability of myoblasts to fuse with one another. This hypothesis is supported by the observation that there is a dose-dependent decrease in fusion of DZ cells when PGE2 is added to commitment medium.

Synergistic Stimulation Of Prostaglandin E2 Production by Calcium lonophore and Protein Kinase C Activator in Rat Granulosa Cells1

The effects of luteinizing hormone-releasing hormone (LHRH) and its putative intracellular mediators on progesterone (P) and prostaglandin E2 (PGE2) formation were studied in rat granulosa cells. A calcium ionophore (A23187), 12-0-tetradecanoylphorbol-13-acetate (TPA), and melittin (a phospholipase A2-stimulator) were used to later intracellular calcium, protein kinase C, and arachidonic acid levels, respectively. During a 5-h incubation, LHRH increased basal P levels but failed to affect the formation of P induced by cholera toxin (CT). On the other hand, both basal and CT-stimulated PGE2 formation were increased by LHRH. Treatment of the cells with A23187 or TPA attenuated the formation of P induced by CT or FSH. By contrast, A23187 or TPA significantly augmented CT- or FSH-stimulated PGE2 formation. Interestingly, the effects of A23187 and TPA on PGE2 were synergistic, whether or not FSH or CT was present during the incubation. This synergy was not observed with regard to P formation. Melittin also increased basal P and PGE2 levels, and enhanced the stimulation of PGE2 by A23187 or TPA. However, in the combined presence of A23187 and TPA, melittin failed to further enhance the high levels of PGE2 accumulated. These findings further support a role for the intracellular calcium, protein kinase C, and arachidonic acid metabolic pathways in the multiple actions of LHRH in the ovary.

Elevated plasma prostaglandin E2 levels in schizophrenia.

Plasma levels of prostaglandin E2 (PGE2) were determined with radioimmunoassay in 40 DSM-III schizophrenics, 15 patients with other mental disorders, and 23 normal controls. The mean value of plasma immunoreactivity of PGE2 was significantly higher in the schizophrenic patients than in the normal controls. Schizophrenic patients with high plasma PGE2 levels had more guilt feelings and hallucinatory behavior on BPRS, relatively successful heterosexual relations, and a higher incidence of birth complications.

Increased in vitro bone resorption by monocytes in the hyper-immunoglobulin E syndrome.

Children with the hyper-immunoglobulinemia E syndrome are prone to bone fractures. We determined bone density in six patients with hyper-IgE syndrome using photon absorptiometry. All six patients had significantly reduced bone density compared with age- and sex-matched controls. The capacity of peripheral blood monocytes to degrade 45Ca-labeled bone in vitro was studied. The mean percent 45Ca release in four hyper-IgE patients (40.8 +/- 8.6) was significantly higher (p less than 0.01) than in ten age-matched healthy control subjects (7.1 +/- 2.6), seven age-matched patients with recurrent infections (7.9 +/- 1.6), or nine patients with severe atopic dermatitis and elevated serum IgE levels (5.8 +/- 1.3). Monocytes from four of four patients studied spontaneously released abnormally high levels of prostaglandin E2. Bone degradation by these monocytes was significantly reduced in the presence of 10(-6) M indomethacin in vitro. Administration of aspirin in vivo to two hyper-IgE patients reduced boned degradation by their monocytes to normal levels. These results suggest that monocytes from patients with hyper-IgE syndrome are activated to resorb bone via products of the prostaglandin synthase (cyclooxygenase) pathway. The activation of cells in the monocyte/macrophage family to resorb bone may contribute to the osteopenia observed in hyper-IgE syndrome.

Formation of a synovial-like membrane at the bone-cement interface. Its role in bone resorption and implant loosening after total hip replacement.

Histologic evaluation of tissue surrounding the loosened components after joint replacement reveals the presence of a synovial-like lining adjacent to the polymethyl methacrylate cement. The tissue is heavily infiltrated with particulate cement as well as polyethylene associated with a foreign body-type giant cell reaction. That this tissue response may be responsible for the bone lysis associated with loosening is suggested by the demonstration of high prostaglandin E2 levels and enhanced bone resorbing activity in the tissue culture medium of fragments from this membrane.

Prostagladin E2in tears

Prostaglandin E2 (PGE2) concentration in tears was measured before and following cataract extraction, during acute anterior uveitis and in patients with chronic conjunctival complaints. Following cataract extraction a significant increased PGE2 level in tears was observed, returning towards normal level within two weeks. In patients with acute anterior uveitis low levels of PGE2 was found in tears. Half of the patients with chronic conjunctival complaints exhibited high levels of PGE2. Conjunctiva is proposed as a likely source of PGE2 in tears.

Distinct role of neonatal and adult monocytes in the regulation of the in vitro antigen-induced plaque-forming cell response in man.

Mononuclear cells from human cord blood (CBMC) are able to mount an antigen-specific IgM plaque-forming cell (PFC) response after primary in vitro stimulation with the T cell-dependent antigen ovalbumin (OA). The antigen dose-response relationship for the induction of PFC in cultures of CBMC is represented by a bell-shaped curve comparable to that found for mononuclear cells from adult peripheral blood (adult PBMC). The dose of OA optimal for the induction of a response in cultures of CBMC consistently, however, is 100-fold lower than the antigen dose optimal for adult PBMC (0.03 microgram OA/ml vs 3.0 micrograms OA/ml). Results obtained from co-culture experiments in which semiallogeneic combinations of parental/neonatal lymphocytes and monocytes were stimulated with a variable dose of OA indicate that the adherent cell (AC) plays a pivotal role in the establishment of the optimum antigen dose. From experiments using antigen-pulsed AC, it was concluded that neonatal and adult AC differ in their antigen handling capacity. In the presence of the prostaglandin synthetase inhibitor indomethacin the antigen dose-response relationship for the induction of PFC in cultures of CBMC shifts to an "adult type" of curve. From pulsing experiments it emerges that indomethacin affects the interaction between antigen and monocytes. Indomethacin causes an enhancement of the expression of HLA-DR at the surface of neonatal as well as adult AC; this can be down regulated by the addition of prostaglandin E2 (PGE2). The addition of PGE2 to cultures of adult PBMC leads to a shift of the optimal antigen dose for induction of PFC toward lower concentrations. Although higher levels of PGE2 were measured in the supernatant of cultured neonatal AC compared with adult AC, it seems unlikely that this observation can explain the distinct antigen dose-response relationship for the induction of a PFC response in cultures of CBMC.

Tumor-associated prostaglandins in patients with primary breast cancer: Relationship to clinical parameters

Determination of the levels of prostaglandin E2 (PGE2) and PGF2α were carried out using homogenized primary human breast tumors. Measurable levels of both prostaglandins were found in all but one tumor examined. In most samples, the absolute PGF2α level was higher than that of PGE2. Higher PGE2 levels are more often seen in postmenopausal women than in pre- or perimenopausal patients, though among postmenopausal women, PGE2 levels do not correlate with age. Thus, the ratio of PGF:PGE is higher in pre/perimenopausal women than in postmenopausal women. Differences in PGF2α do not appear to be associated with age or menopausal status.

The effects of long-chain monoenes on prostaglandin E2 synthesis by rat skin.

AbstractIn order to ascertain whether the dermal lesions observed in male rats fed rapeseed oils are due to impaired prostaglandin biosynthesis, endogenous levels of prostaglandin E2 (PGE2) in skin and the capacity of this tissue to synthesize PGE2 from arachidonic acid was investigated. Male Sprague‐Dawley rats were fed from weaning for 8 weeks either a standard rat diet (chow) or semisynthetic diets containing 20% by weight of the following fat sources: corn oil; commercial lard; commercial lard to which was added 5.4% free erucic acid; rendered pig fat; or the following rapeseed oils:Brassica napus var. Zephyr;B. campestris var. Span;B. campestris var. Arlo (15%) and var. Echo (85%) designated HEAR (high erucic acid rapeseed). The long‐chain monoene content (18∶1, 20∶1, and 22∶1) of the diets fed ranged from 30 to 71 mole % and that of skin from 27 to 74 mole %. A significant (P<0.01) correlation was found between the level of 18∶2n−6 in the diet and the endogenous PGE2 levels in skin and the capacity of this tissue to synthesize PGE2. No relationship was found between these two PGE2 parameters and the level of erucic acid in the diet. The rate of turnover of PGE2 appeared to be lower in rats fed rapeseed oil as evidenced by the relatively high endogenous PGE2 levels when these oils were fed (96 to 105 μg/g). On the other hand, the lowest capacity for PGE2 synthesis was found with skin from rats fed Zephyr rapeseed oil, rats which also had the most severe incidence of hair loss and dermal lesions. Significant (P<0.01) negative correlations were observed between the level of monoenes and specifically the level of oleic (18∶1n−9) acid in the diets and PGE2 synthesis capacity of skin, possibly confirming the known inhibitory effect of 18∶1n−9 on the prostaglandin synthesizing enzyme system.