PROSTAGLANDIlVSLEUKOTRJENES ANDEBSEZVTIALFATTYACIDS Prostaglandins Leukottienes and Essential 0 Longman Group UK Ltd 1992
Modulation of Prostacyclin Production by Cytokines in Vascular Endothelial Cells A. RistimZki*’ and L. Viinikka” *Children’s Hospital and ‘Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki. SF-00290 Helsinki, Finland (Reprint requests to LV) factors, monokines, and lymphokines (1 l), are important modulators of PG12 synthesis by vascular endothelium (Tables 1 & 2). Cytokines are released from aggregating platelets, from activated leukocytes, and from cells present in the vascular wall (Fig.), and both EC and smooth muscle cells have receptors for many of these agents (12-14). Thus, cytokines may be important modulators of blood vessel functions. The present review was written to clarify the roles of these peptides in regulating the production of PGIz and other prostanoids in vascular EC.
INTRODUCTION The luminal surface of all blood vessels is covered with a monolayer of endothelial cells (EC). The vascular endothelium interacts with the components of the blood and with other cells of the vessel wall and these interactions modulate the function of leukocytes, platelets, and smooth muscle cells (l-3). One function of the vascular endothelium is to adjust the blood flow by synthesizing a variety of biologically active substances that regulate blood coagulation, fibrinolysis, platelet adhesion and aggregation, and relaxation and contraction of blood vessels (l-3). The best known endotheliumderived antiplatelet and vasodilatory factor is prostacyclin (PGI,), which is the major arachidonic acid product of EC, except in some microvascular EC (3-5). In addition, PGI, inhibits the growth of human vascular smooth muscle cells in vivo (6), possibly by preventing the release of mitogens from macrophages, platelets, and EC (7), and by directly inhibiting smooth muscle synthesis of DNA (8). Furthermore, PGI, stimulates fibrinolytic activity in atherosclerotic patients (9) and inhibits foam cell formation and cholesterol accumulation in the vascular wall (7, 10). All this suggests that PGI, is an important antiatherogenic agent, yet little is known about how its production is regulated. However, recent data show that cytokines, which include polypeptide growth Table 1 Cytokines (PGI?) in HUVEC
that modulate production
Effect on PGI, production
Angiogenin EGF FGF acidic FGF basic IL-1 (a or 8) IL-2 TGF-a TGF-B TNF-a TNF-B VASIVEGF
Stimulatory Stimulatory Inhibitory Inhibitory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory
112 67 84.95-99 95 1%27,30-32 38 62 84 21, 22, 30,41 30 111
Interleukins and tumor necrosis factors Interleukin 1 (IL-l) is a single-chain polypeptide with a molecular weight (MW) of approximately 17 kD (15). Two IL-l gene products have been cloned, IL-la and IL-lb; they show limited structural homology, do not posses the signal sequence needed for a peptide to be secreted into the extracellular space, bind to the same receptor. and exhibit similar biological activities Table 2 Cytokines that modulate production of prostanoids vascular endothelial cells (EC) other than HUVEC Cytokine
Angiogenin EGF FGF acidic
FGF basic IFN-a IFN-y IL-1 (cc or p, IL-2 IL-6 TNF-a
Origin of EC
Bovine adrenal microvessels Canine fundic mucosal microvessels Bovine glomerular Bovine aorta and human retinal microvessels Bovine aorta and human retinal microvessels Bovine aorta Rabbit coronary microvessels Rat heart microvessels Rabbit coronary microvessels Human dermal microvessels Bovine aorta Bovine carotid artery Bovine pulmonary artery and bovine lung microvessels Human umbilical artery
Effect on prostanoid production
Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Inhibitory Stimulatory
47 33 48 33 34, 35 31. 38 39 42
Prostaglandins Leukotrienes and Essential Fatty Acids
GFs, IL-l, TGF-I3
Smooth musde eeU
Sources of cytokines that modulate prostanoid production in vascular endothelial cells.
(15, 16). These peptides are principally produced by activated macrophages, but other leukocytes, fibroblasts, vascular smooth muscle cells, and EC can also synthesize them (15). In addition, IL-1s are also associated with platelet membranes after thrombin activation (17). IL-1s mediate inflammation and many of their effects, including hypotension and fever, are dependent on prostanoid synthesis (15). Factors derived from activated human monocytes stimulated the production of PGI, and prostaglandin E, (PGE,) in human umbilical vein EC (HUVEC), in human and rat aortic smooth muscle cells and in human dermal fibroblasts (18, 19). This activity derived from monocytes was mimicked by purified human IL-l and was indistinguishable after separation by charge or by size fiom IL-l activity as measured by a bioassay for IL-l. Several groups have confirmed the stimulatory effect of IL-l on PG12 synthesis by HUVEC, using natural IL-l (20), human recombinant IL-la (20-24), and IL-l/3 (20, 22, 25-27). These different IL-l species are equipotent in stimulating EC prostanoid production (20, 22). IL-l stimulates synthesis of prostanoids in EC slowly, after incubation for several hours (19,23). When used for repeated treatments, IL-I shows no tachyphylaxis (25,26) in contrast to fast stimulators of prostanoid release, such as arachidonic acid, thrombin, and histamine (28, 29). In addition to increasing basal production of prostanoids in HUVEC (18, 19) preincubation with IL- 1 enhances the thrombin- and histamine-induced rapid release of PGI,, PGE,, and PGF2, (25, 30, 31). Furthermore, IL-l increases endogenous release of arachidonic acid (25) enhances recovery of PG12 synthesis after the irreversible inhibition of cyclooxygenase by aspirin (25), upregulates the expression of cyclooxygenase
mRNA at transcriptional level (24, 32), increases the amount of immunoreactive cyclooxygenase (32), and stimulates the fast release of PG12 induced by arachidonic acid (25) and PGH, (30). These results suggest that, at least in HUVEC, IL-l stimulates the activity of phospholipase AZ, cyclooxygenase, and PGIZ synthase, i.e. all the enzymatic steps involved in the synthesis of PG12. IL-l stimulates PGI, and/or PGE, production, not only in HUVEC, but also in EC from rabbit coronary microvessels (33) and in human dermal microvascular EC (34). IL-2 is a secretory peptide of T lymphocytes with a MW of approximately 15 kD and it binds to a receptor of its own (36). In contrast to an earlier finding by Rossi et al (19), IL-2 stimulates PGIZ production in an RNA and protein-synthesis-dependent manner, enhances the recovery of PGI, production after aspirin treatment, and increases the amount of immunoreactive cyclooxygenase in bovine aortic EC and/or in HUVEC (37, 38). IL-6 is a secretory peptide with a MW of between 23-30 kD, which binds to a receptor of its own (36). It is produced by a wide variety of cells, including macrophages, T and B lymphocytes, and EC. IL-6 inhibits production of PGI, in bovine carotid artery EC at the cyclooxygenase level (39), but does not affect PGI, synthesis in HUVEC (40). Tumor necrosis factor a (TNF-o, also known as cachectin) is, like IL-l, a single-chain polypeptide with a MW of approximately 17 kD, a product of activated macrophages, a mediator of inflammation, and it possesses no signal sequence (15, 16). Although IL-l and TNF-a have many biological activities in common (including prostanoid dependent hypotensive and pyrogenie effects), they are not structurally related and they
Modulation of Prostacyclin Production by Cytokines in Vascular Endothelial Cells
bind to separate receptors. TNF-a and the structurally related TNF-P (also known as lymphotoxin, which is a product of activated T lymphocytes and has a receptor with TNF-cl in common, (13)), stimulate synthesis of PGI? in HUVEC in a similar manner to although IL-l is more potent (21, 22, 27, 30,41). A combination of IL-l and TNF-a enhances PGI, synthesis additively (22). TNF-a also stimulates prostanoid synthesis in bovine pulmonary artery EC and in microvascular EC of bovine lung (42), but not in sinusoidal liver EC of guinea-pig (41). In a bovine EC line, TNF-a enhances phospholipase A? activity within minutes, which was suggested to be dependent on synthesis of a phospholipase AZ-activating protein (43). Interestingly, rapid release of PGI, was also found in human EC from umbilical arteries (44).
In terferons Three main types of interferon exist (IFN-a, IFN-p, and IFN-y) and their MWs are between 17-25 kD (45). IFNa, which actually is a group of several homologous peptides, and IFN-P share the same receptor, whereas IFN-y has a receptor of its own. IFN-a is most efficiently produced by activated macrophages, IFN-p by fibroblasts and epithelial cells, and IFN-)I by activated T lymphocytes (45), but IFN-a and IFN-P are also produced by EC (46). PG12 synthesis is stimulated by IFN-a in bovine aortic EC (47) and by IFN-y in rabbit coronary microvessel EC (33) and in rat heart microvascular EC (48). None of these IFNs had any effect on PGI? synthesis by HUVEC ( 19).
Epidermal growth factor and transforming growth factor-cc Epidermal growth factor (EGF) and transforming growth factor a (TGF-a) are single-chain polypeptides with MWs of approximately 6 kD (49, 50). Human EGF and TGF-cr have 42% amino acid sequence homology and both bind to the EGF receptor and stimulate an intrinsic tyrosine kinase (50, 51). EGF is abundant in human urine (also known as P-urogastrone), milk, saliva (49), and blood, in which it is stored in platelets and released from them in a cytoskeleton-dependent manner when the platelets aggregate (52-56). TGF-a is mainly a product of solid tumors (57) and embryonic tissues (58), and is produced by only a few cell types of nonmalignant adult human origin, such as keratinocytes (59) and macrophages (60). Although EGF and TGF-a bind to the same receptor with similar affinities, and many of their effects are the same, including induction of EC growth (61,62), TGF-a is more potent than EGF in increasing regional blood flow (63). in promoting angiogenesis (61). in accelerating wound healing (64), and in stimulating prostanoid-synthesis-dependent and -independent bone resorption (65. 66). EGF and TGF-a stimulate the synthesis of PGI, by HUVEC in a protein-synthesis-dependent manner. TGF-a being 10-100 times more
potent than EGF (62, 67). In addition, EGF stimulates synthesis of PGE? in canine fundic mucosal microvessel EC (68). and EGF-induced production of prostanoids may mediate its gastric mucosal protective activity in the rat (69, 70). EGF also enhances recovery of PGI? synthesis after aspirin treatment in rabbit aortas (71) and in cultured rat aortic smooth muscle cells (72).
TGF-/31 TGF-Pl is a homodimeric peptide with a MW of approximately 25 kD, which is the principal member of the TGF-P family of homologous peptides (73). This multifunctional peptide is synthesized by a variety of normal and transformed cells (74, 75). Human platelets contain TGF-Pl in large amounts (76, 77), and it is also released by macrophages and by EC (12, 14). Although TGF-Pl is usually liberated from cultured cells (78, 79) and human platelets (80) as an inactive compound, plasmin can activate a small pool of this latent molecule (81). Interestingly, TGF-Pl is activated in co-cultures of endothelial and smooth muscle cells or pericytes, probably by plasmin (82, 83). Thus, biologically active TGFp 1 may be present in the vascular wall, especially at sites of endothelial injury, where platelets are aggregating and plasmin is present. TGF-Bl stimulates production of PGIl in an RNA- and protein-synthesis-dependent manner in HUVEC, and EGF and TGF-Pl act synergistically (84). A similar synergism has been reported for prostanoid production in cultured mouse osteoblasts (85), an effect that correlates with the amount of immunoreactive cyclooxygenase, and in rat smooth muscle cells (86), an action accompanied with increased production of cyclooxygenase mRNA (87).
Fihroblast growth factors Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) (or heparin-binding growth factor-l and -2, respectively) are single-chain polypeptides with MWs of approximately 16 kD that activate through receptor binding intrinsic tyrosine kinase (88). There is a whole family of FGFs (88). but studies on EC have been made almost exclusively with either aFGF and bFGF. The latter is produced by macrophages. EC, and smooth muscle cells, whereas aFGF is found mainly in neural tissue (12, 14), and to some extent also in EC and vascular smooth muscle cells (89, 90). Both FGFs are potent angiogenic factors, but neither aFGF nor bFGF possesses the signal sequence needed for secretion of a protein into the extracellular space (88). This has led to the hypothesis that these FGFs may normally be present in a storage form, bound to heparin or heparin-like molecules attached to cell membranes or in the extracellular matrix. In fact, bFGF produced by EC is located in the matrix of these cells (9 1, 92). from which it is released by mechanical injury (93) or following degradation by proteases (94).
and Essential Fatty Acids
aFGF or growth supplements containing it, especially in the presence of heparin, inhibit basal (84, 95-97) and agonist-induced (96,97) production of PGI, by HUVEC, as well as serum-induced recovery of PGI? production from aspirin treatment (98). In addition, aFGF inhibits basal and arachidonic acid-induced synthesis of PGE, in bovine glomerular EC (99). The effect of aFGF only appears after incubation for 24 h, and it reduces immunoreactive cyclooxygenase and PG12 synthase activity (97) and inhibits expression of cyclooxygenase mRNA (100). In our experiments, bFGF had no effect on endothelial PG12 synthesis during a 24-h incubation (84). This is somewhat unexpected, since bFGF is generally considered to be more potent than aFGF (12, 14, 88). On the other hand, incubation for 48 h with bFGF has been shown to inhibit PGI, synthesis in HUVEC (95). In addition, aFGF shifts the prostanoid production of the microvascular EC (but not that of bovine pulmonary artery EC) from PGI, to other prostanoids (101) and may do so in HUVEC (97). Interestingly, both aFGFand bFGF-stimulated PGI, release by fetal bovine aortic EC and by human retinal capillaries, although these cells did not respond to EGF, TGF-a, or TGF-/3 (102). Platelet-derived growth factor Platelet-derived growth factor (PDGF) is a dimeric molecule with a MW of approximately 30 kD, and is composed of A and B chains, which are assembled as homodimers or heterodimers that activate through a receptor binding intracellular tyrosine kinase (103). PDGF was originally purified from human platelets, but is now known to be produced by several other cell types including macrophages, smooth muscle, and EC (14, 103). Thus, PDGF is likely to be present at the site of a vascular injury. PDGF is a mitogen and it also enhances prostanoid production for many cell types, including fibroblasts and vascular smooth muscle cells (104-106). In contrast to an earlier finding with bovine aortic EC and bovine adrenal capillary EC (104), PDGF does not have an effect on PGI, production by bovine aortic EC (107, 108) or HUVEC (84, 108). This observation is compatible with the absence of PDGF receptors from large vessel EC (103, 109). On the other hand, microvessel EC have PDGF receptors, and PDGF is mitogenic for these cells (109, 110). It remains to be shown whether PDGF stimulates production of PGI, by capillary EC. Other cytokines Vasculotropin/vascular endothelial cell growth factor (VAS/VEGF, also known as vascular permeability factor) is a secretory peptide with a MW of 45 kD with homodimeric structure (111). VAS/VEGF is a member of the PDGF family but, unlike PDGF, it is a specific growth factor for vascular endothelial cells. VAS/VEGF stimulates PGI, synthesis in HUVEC, but only in very high concentrations (111).
Angiogenin is a 45 kD peptide with sequence homology to pancreatic ribonuclease (I 12). It is present in plasma at high concentration, is angiogenic in l~i\~, but does not induce proliferation of endothelial cells. Angiogenin stimulates fast release of PGI, by stimulating phospholipase AZ in EC from bovine adrenal microvessels and in HUVEC (112).
SUMMARY The data presented in this review clearly show that many different cytokines regulate the synthesis of PGI, in vascular EC (Tables 1 & 2). Since these agents are synthesized, stored, and/or released from platelets, leukocytes and cells present in the vascular wall (Fig.), they are to be found at sites of vascular injury and may, through their effect on the synthesis of PGI, and other prostanoids, regulate thrombogenesis and atherogenesis. Despite the mass of detailed data, the picture is still fragmentary. Very little, for instance, is known about the ‘orchestral effects’ of different combinations of cytokines. In addition, it seems that the regulation of PG12 synthesis by cytokines varies with the species and with the type of vasculature from which the cells originated. However, discrepancies may also be due to the use of different culture conditions. Moreover, we must remember that the present data are almost exclusively from in vitro studies, and the representativeness of these results in in vivo situations remains to be clarified. Acknowledgements AR is supported by the Finnish Academy. The valuable comments Professor Olavi Ylikorkala are gratefully acknowledged.
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