Prostaglandin and thromboxane biosynthesis in isolated platelet-free human monocytes: III. The induction of cycloxygenase by colony stimulating factor-1

doi:10.1016/0952-3278(89)90026-4

Prostaglandins, Leukotrienes and Essential Fatty Acids

Volume 36, Issue 2, May 1989, Pages 101-106

https://doi.org/10.1016/0952-3278(89)90026-4 Get rights and content

Abstract

Previous observations showing the presence in the serum of a component capable of regulating prostanoid biosynthesis in human cultured monocytes, have led us to suspect its presence in human platelets. We have purified this serum monocytotropic factor (SMF) and have shown its identity with a component of platelet membranes. Surprisingly its structure appeared to be very similar to that of a polypeptide growth factor never before identified in platelets: the colony stimulating factor-1 (CSF-1 or M-CSF).

Here we show that SMF and CSF-1 have very similar biological properties. Thus, CSF-1 when released from human platelets is capable of triggering the differentiation pathway leading from blood monocytes to resident macrophages. It is likely that cycloxygenase induction plays a pivotal role in these events.

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Soluble factors differ in platelets derived from separate niches: a pilot study comparing the secretome of peripheral blood and bone marrow platelets
2021, Cytotherapy
Citation Excerpt :
Therefore, continued detection of the factors over 6 days and relative changes in cytokine levels in BMP compared with LPP provide insight into the differential secretome of platelets from the respective niches. Although the cell source of the cytokines assayed is variable and not exclusive to platelets, PDGF-AA, bFGF/FGF-2, GM-CSF, HGF, M-CSF, VEGF, TNF-α, IL-1β, IFN-γ, IL-12, IL-4, IL-10, IRAP/IL-1Ra and arginase-1 have all been reported to be released by platelets [25–31]. PDGF-AA, which is preferentially secreted by platelets, was used to normalize cytokines to platelet count.
Platelet-rich plasma (PRP) and bone marrow aspirate are commonly used in orthobiologics for their anti-inflammatory, anabolic/regenerative and immunomodulatory characteristics via platelet degranulation and cell secretions. Although platelets are derived from megakaryocytes in the bone marrow, no attention has been paid to the potential benefits of bone marrow platelets and whether their contents differ from aging platelets in peripheral blood.
In the present study, leukocyte-poor peripheral blood-derived platelets in plasma (LPP) and leukocyte-poor bone marrow platelets in plasma (BMP) were prepared from six donors, activated with calcium chloride, incubated and sampled at day 0, day 3 and day 6. LPP and BMP are platelet preparations intended to evaluate the respective platelet secretomes but are not classified as conventional PRPs, as they are not concentrated to the extent necessary to meet the qualifying criteria. At each time point, 15 growth and immunomodulatory factors were quantitated in LPP and BMP: platelet-derived growth factor AA, basic fibroblast growth factor/fibroblast growth factor 2, granulocyte-macrophage colony-stimulating factor, hepatocyte growth factor, macrophage colony-stimulating factor, stem cell factor, vascular endothelial growth factor, tumor necrosis factor alpha, IL-1β, interferon gamma, IL-4, IL-10, IL-1 receptor antagonist protein, IL-12p40 and arginase-1.
The results illustrate that platelets derived from bone marrow have a unique secretome profile compared with those derived from peripheral blood, with significant differences in anti-inflammatory cytokines, which are associated with monocyte polarization.
Ultimately, bone marrow-derived platelets may be useful as a stand-alone orthobiologic or as an effective adjuvant to autologous cell therapies where anti-inflammatory and anabolic processes are desired, especially with respect to monocyte function.
Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease: Effects of aspirin treatment
2005, American Heart Journal
Citation Excerpt :
Conversely, smokers and nonsmokers had similar levels of prothrombin F1+2 suggesting that smoking may not have a direct effect on thrombin generation in patients with chronic CAD. Experimental studies have shown the ability of M-CSF to promote per se platelet activation4–7,28 in vitro. In a previous study, we have also shown a significant relation between M-CSF and a TXA2 in vivo.21
Smoking is associated with endothelial dysfunction. Cytokines released by injured endothelium promote vascular interactions with leukocytes and platelets. We investigated whether (a) cigarette smoking is linked to increased cytokine production, which may mediate platelet activation and thrombin generation in chronic coronary artery disease (CAD), and (b) aspirin treatment inhibits smoking-related changes on cytokines, platelets, and thrombin.
Plasma macrophage–colony-stimulating factor (M-CSF) and C-reactive protein (CRP) were measured in 100 patients with chronic CAD, 60 of whom were chronic smokers. Prothrombin fragments 1+2 and urinary 11–dehydro-thromboxane B₂ (TXB₂) were additionally measured in 60 of 100 patients (30 of whom were smokers) and in 24 healthy controls. Smokers (n = 20) matched for age, myocardial ischemia, and other risk factors with 20 nonsmokers entered a double-blind crossover trial of aspirin (300 mg/d for 3 weeks) versus placebo. Blood and urine measurements were repeated after each treatment. Compared with nonsmokers, smokers had 3-fold median M-CSF (1499 vs 476 pg/mL), 2-fold CRP (1.5 vs 0.8 mg/L), and higher 11–dehydro-TXB₂ (3.6 vs 2.1 ng/mg creatinine, P < .01 for all comparisons). After aspirin treatment, M-CSF, CRP, 11–dehydro-TXB₂, and prothrombin fragments 1+2 remained higher in smokers compared with nonsmokers despite a significant reduction of these markers by aspirin (P < .05). M-CSF remained related to 11–dehydro-TXB₂ excretion during both treatment phases (P < .01) suggesting that cytokine-mediated thromboxane A₂ production was not altered by aspirin.
Smoking is associated with increased M-CSF, CRP, and platelet activity. Although aspirin treatment reduces the proinflammatory and procoagulant markers in smokers, it does not abolish the proinflammatory effects of smoking in patients with chronic CAD.
Role of arachidonate in monocyte/macrophage function
1996, Advances in Lipobiology
Monocytes/macrophages are a major cellular source of arachidonate. This fatty acid is of considerable biological importance since it serves as the cyclooxygenase and lipoxygenase substrate for production of the eicosanoid inflammatory mediators. It can be released from cells via phospholipase A₂(PLA₂) hydrolysis of membrane phospholipids. This chapter summarizes the current literature regarding the identification, characterization, and regulation of monocyte/macrophage PLA₂s. Additionally, it discusses differential metabolism of the released arachidonate as a function of (a) the stimulus for release, (b) the source and activation state of the macrophages, and (c) the regulation of the cyclooxygenase and lipoxygenase metabolic pathways. Finally, the evidence supporting a role for arachidonate as an autocrine mediator of monocyte/macrophage function is presented. The effects of arachidonate depletion on macrophage trafficking are described in the essential fatty acid deficient mouse and are related to in vitro studies demonstrating an arachidonate requirement for monocyte and macrophage adherence. Additionally, the involvement of arachidonate as an intracellular second messenger is discussed in the context of phagocytosis and membrane fusion.
Post-transcriptional regulation of thromboxane A2 synthase in U937 cells
1995, Biochemical and Biophysical Research Communications
Translation of mRNAs is a process usually tightly coupled to transcription of genes. However, there are examples of mRNA species which accumulate without being translated. Some mRNAs present in oocytes and ferritin mRNA are the most studied models. Studying the biogenesis of thromboxane A2 (TXA2) in the promonocytic line U937, we have noted that in proliferating cells high levels of TXA2 synthase mRNA are detectable by Northern blot, whereas no TXA2 could be recovered in the medium. This has been explained on the basis of Western blot experiments: TXA2 synthase was not detectable in proliferating cells, while a band of about 55 kd appears after treatment with the differentiating agent TPA. Immunofluorescence detection by confocal microscopy was in agreement with Immunoblot results. Thus, in U937 cells, TPA behaves as a regulator of translation of TXA2 synthase mRNA. We have further observed that the induced enzyme in U937 cells has many characteristics in common with the human monocytic enzyme: a long half life (>24 hrs), a marked stability during catalysis and similar Km and Vmax values. Thus, U937 cells are a good model to study the mechanism by which a mRNA is efficiently translated only after differentiation has been triggered.
Thromboxane A<inf>2</inf> synthase activity in platelet free human monocytes
1994, Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism
Soon after platelets, the highest amounts of thromboxane A₂ (TXA₂) can be detected in human monocytes activated by serum. Using platelet-free human monocytes, we have shown that foetal calf serum (FCS) induces prostaglandin H synthase (PGH synthase) after 16 h of incubation, as shown by the use of transcriptional inhibitors and Western blotting. The effect of serum can be in part mimicked by recombinant colony stimulating factor-1 (hr CSF-1). It is not known whether the limiting step leading from arachidonate to TXA2 is represented solely by the level of PGH synthase or also by the level of TXA2 synthase. We approached this problem by using a Western blot specific for the enzyme, as well as by using PGH2 as substrate. The results show that TXA2 synthase is constitutively expressed in monocytes i.e., its levels were high soon after their isolation, and similar to those observed after 24 h of incubation with serum. However TXA2 failed to be synthesized until at least 3 h of incubation, and the pattern of synthesis was dependent on the kinetics of PGH synthase induction. In any condition in which TXA2 synthase was immunodetectable, using PGH2 as substrate a high rate of conversion to TXB2 could be detected. Experiments with actinomycin D and cycloheximide indicate that the half-life of TXA2 synthase was longer than 16 h, therefore much longer than that of PGH synthase, that the gene coding for it is fully active in resting monocytes, and that the conversion of arachidonate to TXA2 induced by serum or CSF-1 is dependent solely on the de novo synthesis of PGH synthase.
Differential turnover of enzymes involved in human monocyte eicosanoid metabolism. Selective inhibition of cyclooxygenase product formation by cycloheximide in the absence of effects on 5-lipoxygenase or phospholipase A<inf>2</inf>
1992, Biochemical Pharmacology
Human monocytes treated with cycloheximide (CHX) demonstrated a concentration- and time-dependent inhibition of prostaglandin E₂ (PGE₂) synthesis and release in response to stimulation with phorbol myristate acetate, ionomycin, serum-treated zymosan, or concanavalin A. The effect of CHX required preincubation and was largely reversible within 2hr. Thromboxane A₂ release was affected similarly but no comparable effects were observed on labeled arachidonic acid release or leukotriene B₄ generation. The PGE₂ response was also inhibited by CHX when monocytes were given exogenous arachidonic acid with or without stimulation. CHX pretreatment also comparably decreased the amount of immunoreactive cyclooxygenase in resting and stimulated monocytes. These data indicate that monocyte cyclooxygenase, in contrast to phospholipase A₂ or 5-lipoxygenase and their regulatory proteins, turns over rapidly and may be a target for up- or down-regulation by pharmacologic or (potentially) physiologic agents which affect protein synthesis or degradation.

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^☆: The first paper is ref. 7, the second one is: M. Chiricolo et al. 1986 EURAGE Immunoregulation in aging (A. Facchini, J. J. Haaijman, F. Labo eds.), pp 247–253, 1986.

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Prostaglandin and thromboxane biosynthesis in isolated platelet-free human monocytes: III. The induction of cycloxygenase by colony stimulating factor-1☆

Abstract

Prost. Leukot. Med.

Biochim. Biophys. Acta.

Blood

J. Immunol. Met.

J. Biol. Chem.

Biochim. Biophys. Acta

Cell. Immunol.

J. Biol. Chem.

J. Biol. Chem.

The granulocyte-macrophage colony stimulating factor

Science

The regulation of mononuclear phagocyte entry into S phase by colony stimulating factor CSF-1

J. Cell Physiol.

Induction of PGE synthesis in normal and neoplastic macrophages: role of CSF(s) distinct from effects on myeloid progenitor cell proliferation

Induced Release and Metabolism of Arachidonic acid from myeloid cells by purified colonystimulating factor

J. Cell. Physiol.

Cleavage of structural proteins during the assembly of the head of Bacteriophage T4

Nature