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Circulation Research. 1999;85:912-918

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(Circulation Research. 1999;85:912.)
© 1999 American Heart Association, Inc.

Cellular Biology

Increase in Prostaglandin E2 Production by Interleukin-1ß in Arterial Smooth Muscle Cells Derived From Patients With Moyamoya Disease

Mari Yamamoto, Masaru Aoyagi, Naomi Fukai, Yoshiharu Matsushima, Kiyotaka Yamamoto

From the Department of Cell Biology (M.Y., M.A., N.F., K.Y.), Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo; and Department of Neurosurgery (M.A., Y.M.), Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Correspondence to Kiyotaka Yamamoto, PhD, Department of Cell Biology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173, Japan. E-mail kyama{at}tmig.or.jp


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract—Moyamoya disease is a progressive cerebrovascular occlusive disease that primarily affects children. The cause is unknown. We examined the production of prostanoids and the expression of cyclooxygenase-2 (COX-2) in cultured arterial smooth muscle cells (SMCs) derived from patients with moyamoya disease. Twelve moyamoya and 8 control cell strains were examined. The steady-state levels of prostanoids in the culture medium did not differ between moyamoya and control SMCs. When the cells were stimulated with interleukin-1ß (IL-1ß), prostaglandin E2 (PGE2) release into the medium was significantly greater from moyamoya SMCs than from control SMCs, whereas the amounts of prostacyclin and thromboxane B2 did not differ. IL-1ß–induced PGE2 production by moyamoya SMCs was completely blocked by the addition of indomethacin or NS-398. IL-1ß significantly stimulated cell migration and DNA synthesis in control SMCs but had an inhibitory effect on moyamoya SMCs. The inhibitory effects on the growth and migration of moyamoya SMCs were caused by excessive secretion of PGE2 and was reversed with indomethacin treatment. Immunofluorescence studies and Western blot analysis showed greater amounts of COX-2 protein expression in IL-1ß–stimulated moyamoya SMCs. These findings suggest that moyamoya SMCs respond to inflammatory stimuli to produce excess amounts of PGE2 through the activation of COX-2, which increases vascular permeability and decreases vascular tone. This facilitates the exposure of vessels to blood constituents and promotes the development of intimal thickening in moyamoya disease.


Key Words: interleukin • moyamoya disease • muscle, smooth • prostaglandin


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Moyamoya disease is an unusual form of chronic cerebrovascular occlusive disease that is characterized by progressive stenosis or occlusion at the distal ends of the bilateral internal carotid arteries.1 2 The disease peaks or primarily occurs during the first decade of life, and the neurological symptoms depend on the specific arteries that are occluded.3 The cause of the disease remains unknown. The findings that the incidence of the disease is highest in, but not confined to, the Japanese4 5 and that the condition is frequently familial6 7 suggest the involvement of a genetic factor in its pathogenesis. Previous reports and our findings suggest the involvement of systemic as well as intracranial arteries in moyamoya disease.8 9 10

The migration of medial smooth muscle cells (SMCs) and their proliferation in the intimal layer may occur in response to injury of the vascular wall.11 Recent evidence12 suggests a role for chronic inflammatory stimuli in SMC proliferation in the thickened intima of patients with moyamoya disease. The inflammatory response at the sites of injury and infiltration involves the activation of many cytokines in the vascular wall, including interleukin-1 (IL-1), interferon-{gamma}, and tumor necrosis factor-{alpha}.11 13 14 The prostanoids represent a diverse group of autocrine and paracrine hormones that are important mediators of many cellular functions15 16 17 In the vasculature, prostacyclin (prostaglandin [PG]I2) and thromboxane A2 act in opposite directions in the maintenance of normal homeostasis and vascular tone. PGE2 may increase vascular permeability and decrease vascular tone.18 Nitric oxide (NO), which is known to be an endothelium-derived relaxing factor, regulates vascular tone and inhibits SMC migration.19 20 When stimulated by proinflammatory cytokines such as IL-1, SMCs express cyclooxygenase-2 (COX-2) and produce PGE2 and express inducible NO synthetase and release NO.21 22 IL-1, which is produced mainly by induced macrophages and monocytes, functions in the generation of systemic and local responses to infection, injury, and immunologic challenges. The unregulated local production of PGs and NO may be responsible for various pathological processes in the vascular wall.20 23 24 25 Based on the assumption that functional alterations in vascular wall cells are involved in the development of intimal thickening in moyamoya disease, we investigated cultured SMCs derived from patients with moyamoya disease.26 27 We recently found that moyamoya SMCs show distinct migratory and proliferative responses through an NO-independent pathway when stimulated by IL-1.28 In the present study, we examined prostanoid production and COX-2 expression in IL-1ß–stimulated SMCs derived from patients with moyamoya disease and compared the results with those in SMCs from age-matched control subjects. We show that the distinct responses of moyamoya SMCs to inflammatory stimuli may contribute to the pathological process in the vascular wall of patients with moyamoya disease.


*    Materials and Methods
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 *Materials and Methods
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Cell Culture
Arterial SMC strains from patients with moyamoya disease (HMSMC) and from control subjects (HCSMC) were established as described previously.26 We used 12 SMC strains from patients with moyamoya disease and 8 strains from control subjects (Table 1Down).


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  		Table 1. Established Strains of Arterial SMCs Derived From Patients With Moyamoya Disease (HMSMC) and Control Patients (HCSMC)

The cells were cultured in 5 mL of Eagle’s MEM (GIBCO) supplemented with 15% FBS (Biocell) at 37°C under humidified 5% CO2/95% air and subcultured at a 1:2 split ratio. For the present study, we used cells at 8 to 14 passages.29

Determination of Prostanoid Production
Medium was replaced with fresh medium containing 0.5% FBS and 500 U/mL IL-1ß (Otsuka Pharmaceutical) with or without 1 µg/mL indomethacin (Sigma Chemical Co), a nonselective COX inhibitor; 1 µmol/L NS-398 (BIOMOL Research Laboratories), a COX-2–selective inhibitor30 ; or 5 µmol/L arachidonic acid (AA; Sigma Chemical Co), and the cells were incubated for 48 hours at 37°C. PGE2, PGI2, and thromboxane (TX)B2 secreted into the medium were measured with the use of enzyme immunoassay kits for PGE2, 6-keto-PGF1{alpha}, and TXB2 (Cayman Chemical), respectively.

Migration Assay
SMC migration was monitored in a microchemotaxis chamber (Neuro Probe) with the use of polycarbonate membranes with 8-µm pores, as described previously.28 Cell suspension was placed in the upper compartment with or without indomethacin (1 µg/mL). The lower compartment contained MEM containing 2% FBS and test reagents (500 U/mL IL-1ß and 0.4 to 200 nmol/L PGE2; Paesel). The samples were incubated in a CO2 incubator for 18 hours at 37°C.

Incorporation of 5-Bromo-2'-Deoxyuridine Into Cellular DNA
5-Bromo-2'-deoxyuridine (BrdU) incorporation was measured with an immunoperoxidase technique (Amersham Corp), as previously described.31 Quiescent SMCs were incubated in MEM containing 0.5% FBS, test reagents, and a labeling regent (BrdU) for 48 hours. The test reagents were IL-1ß (500 U/mL), indomethacin (1 µg/mL), and PGE2 (0.4 to 200 nmol/L).

Immunocytochemistry
Quiescent SMCs were incubated with IL-1ß (500 U/mL) for 9 hours and fixed in acetone/methanol (1:1) at 4°C for 30 minutes. The cells were preincubated with a 1:250 dilution of normal rabbit serum at 24°C for 30 minutes, with a 1:250 dilution of goat anti–COX-1 or anti–COX-2 antibody (Santa Cruz Biotechnology) at 24°C for 1 hour, and then with a 1:250 dilution of rhodamine-conjugated rabbit anti-goat IgG (ICN Biomedicals) at 24°C for 45 minutes.

Western Blot Analysis
Western blot analysis was performed with 10% acrylamide gels, as described previously.32 After blocking, membranes were incubated with a 1:250 dilution of goat anti–COX-1 or anti–COX-2 antibody at 24°C for 1 hour and then with a 1:500 dilution of peroxidase-conjugated rabbit anti-goat IgG (ICN Biomedicals) at 24°C for 45 minutes.

Statistical Analysis
Values are given as mean±SD. Differences in data between groups were assessed with the use of an unpaired t test. A value of P<0.05 was considered statistically significant.

An expanded Materials and Methods section is available online at http://www.circresaha.org.


*    Results
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 up arrowAbstract
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 up arrowMaterials and Methods
 *Results
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Prostanoid Production in Culture Medium of Arterial SMCs Derived From Patients With Moyamoya Disease
The steady-state levels of PGE2, PGI2, and TXB2 production in HMSMC strains were low and not significantly different from those in HCSMC strains (Figure 1Down). Although IL-1ß promoted both PGE2 and PGI2 production in the culture medium of HCSMC and HMSMC strains, the levels of IL-1ß–induced PGE2 production in HMSMC (44.8-fold) were significantly greater than those in HCSMC (10.2-fold) strains. In contrast, the levels of IL-1ß–induced PGI2 production did not differ significantly between HCSMC and HMSMC strains (Figure 1Down). IL-1ß did not stimulate TXB2 production by either the HCSMC or HMSMC strain. The addition of indomethacin (1 µg/mL) completely blocked IL-1ß–induced prostanoid production by both HMSMC and HCSMC strains (Figure 1Down). The simultaneous addition of NS-398 (1 µmol/L) with the cytokine completely suppressed PGE2 and PGI2 production by both HMSMC and HCSMC strains (Figure 1Down).



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  		Figure 1. Release of prostanoids into medium of arterial SMCs derived from moyamoya patients (HMSMC) and control subjects (HCSMC). SMCs grown to confluence were washed with MEM containing 0.5% FBS. Medium was replaced with fresh MEM containing 0.5% FBS and IL-1ß (500 U/mL) with or without indomethacin (Indo; 1 µg/mL) or NS-398 (1 µmol/L), and cells were incubated for 48 hours at 37°C. PGE2, PGI2, and TXB2 secreted into medium were measured with enzyme immunoassay kits. Columns show mean and SD values for HCSMC (n=8) and HMSMC (n=12). *P<0.01 and **P<0.001 compared with cells without IL-1ß (controls) and with cells from control subjects (HCSMC) by unpaired t test.

We then compared the conversion of exogenous AA (5 µmol/L) by arterial SMCs from patients with moyamoya disease and from control subjects. As shown in Figure 2Down, PGE2 production by HMSMC strains was clearly stimulated by the addition of AA, but the amount did not differ significantly from that produced by control strains (Figure 2Down). The AA-stimulated PGE2 production in HMSMC strains was significantly increased by IL-1ß compared with that in HCSMC strains.



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  		Figure 2. PGE2 production by HMSMC and HCSMC. SMCs were incubated with fresh MEM containing 0.5% FBS, AA (5 µmol/L), and IL-1ß (500 U/mL) for 48 hours at 37°C. PGE2 secreted into medium was measured with enzyme immunoassay kit. Columns show mean and SD values for HCSMC (n=8) and HMSMC (n=12). *P<0.01 and **P<0.001 compared with cells without IL-1ß (controls) and with cells from control subjects (HCSMC) by unpaired t test.

Cell Migration and DNA Synthesis
The number of migrating cells in serum-deficient medium without test mitogens (controls) did not differ between HCSMC (80.4±17.2) and HMSMC (81.1±11.1) strains. IL-1ß stimulated cell migration in HCSMC strains, although it significantly inhibited migration in HMSMC strains (Table 2Down). IL-1ß also stimulated BrdU incorporation into cellular DNA in control SMCs but had a rather inhibitory effect on DNA synthesis in moyamoya SMCs (Table 2Down). The basal labeling indices (controls) were 17.0±4.8% for HCSMC strains and 18.4±5.0% for HMSMC strains (P=NS). When prostanoid synthesis was inhibited with indomethacin, IL-1ß significantly stimulated cell migration and BrdU incorporation in both HMSMC and HCSMC strains (Table 2Down). High concentrations (20 to 200 nmol/L) of exogenous PGE2 induced the inhibition of IL-1ß–stimulated cell migration and DNA synthesis in HCSMC and HMSMC strains, but lower concentrations (0.4 to 4 nmol/L) had no detectable inhibitory effects (Table 2Down). The higher PGE2 concentrations correspond to those produced by IL-1ß–stimulated HMSMC, and the lower concentrations correspond to those produced by IL-1ß–stimulated HCSMC (Figure 1Up).


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  		Table 2. Effects of Exogenous PGE2 on Migration of and BrdU Incorporation Into HMSMC and HCSMC Strains

COX-2 Expression
We examined the expression of COX-1 and COX-2 proteins in cultured arterial SMCs through immunofluorescence study. No positive immunostaining was found in both moyamoya and control SMCs in the absence of the primary antibody or in the nonimmune goat IgG (Figure 3Down, A and B). COX-2 protein was hardly detected in moyamoya and control SMCs grown to confluence (Figure 3Down, C and D). IL-1ß stimulated the expression of COX-2 protein in both moyamoya and control SMCs (Figure 3Down, E and F); however, the increase in the number of COX-2–positive cells was significantly (P<0.001) greater in moyamoya SMCs (16.5±2.6%) than in control SMCs (5.3±2.1%). In contrast, COX-1 immunoreactivity did not differ between moyamoya (6.5±3.2%) and control (4.8±2.3%) SMCs in the presence of IL-1ß and between moyamoya (5.9±3.7%) and control (5.0±1.8%) SMCs in the absence of IL-1ß.



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  		Figure 3. Immunostaining for COX-2 protein on moyamoya (B, D, and F) and control (A, C, and E) SMCs. Cells grown on Lab-Tek chamber glass slides were incubated with fresh medium with (E and F) or without (C and D) IL-1ß (500 U/mL) for 9 hours. The cells fixed in acetone/methanol were incubated with (C through F) or without (A and B) an anti–COX-2 antibody and then with rhodamine-conjugated anti-goat IgG. Confocal micrograms were taken with a Bio-Rad MRC 1000 laser scanning confocal imaging system connected to a Zeiss Axiophot. Positive immunostaining for COX-2 protein is observed in cell cytoplasm. Bar, 50 µm.

Immunoblot analysis showed that the expression of COX-2 protein was hardly detected in homogenates of moyamoya and control SMCs in the absence of IL-1ß (Figure 4Down). The immunoreactive band to COX-2 increased clearly in both moyamoya and control SMCs in the presence of IL-1ß, although the expression of COX-1 protein was not stimulated by IL-1ß (Figure 4Down). The relative density of the COX-2 protein in moyamoya cell strains was significantly (P<0.001) higher than that in control cell strains (Figure 4Down).



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  		Figure 4. Western blot analysis of COX-1 and COX-2 proteins in moyamoya and control SMCs. Equal amounts of protein were loaded onto 12% slab gels and electroblotted to P membranes. Membranes were incubated with anti–COX-1 or anti–COX-2 antibody and developed with 4CN-plus. A, Expression of COX-2 protein by IL-1ß. Lanes 1 through 4 indicate HCSMC-4, -7, -16, and -18 strains; and lanes 5 through 10, HMSMC-3, -18, -23, -30, -32, and -36 strains. B, Densitometric scanning was performed to compare relative protein levels. Experimental varieties were tested in three separate assays. Columns show the mean and SD values for HCSMC and HMSMC strains. *P<0.002 and **P<0.0001 compared with cells without IL-1ß (controls) and cells from control subjects (HCSMC) by independent Student t test.


*    Discussion
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 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
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Previous studies3 33 have suggested that moyamoya disease is an acquired disorder in which both an immunologic vascular reaction and subsequent inflammation play important roles. Recent evidence12 indicates that inflammatory stimuli and the subsequent response of inflammatory cells may produce a proliferative response in SMCs in the thickened intima of patients with moyamoya disease. In the present study, we examined the production of prostanoids, which act as mediators that modulate vascular functions when stimulated by proinflammatory cytokines such as IL-1,19 34 35 in arterial SMCs derived from patients with moyamoya disease. IL-1ß stimulates PGE2 and PGI2 production in both moyamoya and control SMCs. When stimulated by IL-1ß, the levels of PGI2 production do not differ between moyamoya and control SMCs. However, the level of IL-1ß–stimulated PGE2 production by moyamoya SMCs is significantly greater than that by control SMCs. NO stimulated by IL-1 also acts as a mediator that modulates vascular functions,19 34 35 but IL-1–induced NO production is found to be almost the same in HMSMC and HCSMC strains.28

IL-1 is a multipotent inflammatory mediator that may play a central role in vascular pathophysiology.36 37 Previous reports indicate that IL-1 stimulates the migration and proliferation of aortic SMCs,38 39 whereas others have shown it to lack mitogenic effects on vascular SMCs.34 40 IL-1 reportedly stimulates cells to produce platelet-derived growth factor-AA,39 a positively affecting mitogen, and stimulates cells to produce PGE234 and NO,19 41 both of which have inhibitory effects on cell mitogenesis. As we reported recently,28 IL-1ß was found to significantly stimulate cell migration and DNA synthesis in control SMCs, whereas it inhibits cell migration and DNA synthesis in moyamoya SMCs. The inhibitory effect of IL-1ß on cell migration and DNA synthesis in moyamoya SMCs corresponds to the elevated levels of PGE2, but not NO, production. Indomethacin treatment suppresses PG synthesis and results in stimulatory effects by IL-1ß on cell migration and DNA synthesis in moyamoya SMCs. Furthermore, the higher concentrations of exogenous PGE2, corresponding to the endogenous PGE2 levels produced by IL-1ß–stimulated moyamoya SMCs, in the presence of indomethacin inhibits IL-1ß–stimulated migration and DNA synthesis in both moyamoya and control SMCs. Taken together, it is most likely that IL-1ß fails to stimulate the migration and proliferation of moyamoya SMCs due to excessive autocrine PGE2 production from moyamoya SMCs.

The synthesis of PGs that have diverse biological effects on the vasculature is regulated by two successive metabolic steps: the release of AA from membranous phospholipids and its conversion to PGs.16 17 Two COX isoforms, COX-1 and COX-2, are the key enzymes that convert AA to PGs. COX-1 is constitutively expressed in most tissues. In healthy vessels, PGI2, which is a protective, "antiatherogenic" mediator, is formed predominantly in the endothelial layer via the actions of constitutive COX-1.42 In contrast, COX-2 is undetectable under physiological conditions but is markedly induced by several cytokines and growth factors in vascular cells.43 44 COX-2 limits the proliferation of human vascular SMCs.45 COX-2 is thought to be involved in the overproduction of prostanoids under pathological conditions such as acute and chronic inflammatory disorders and appears to be expressed only by specific stimulatory events.17 46 Studies in animals show that vessels damaged by angioplasty or pinch express COX-2, an event that may account for an increased release of protective PGI2.47 Bishop-Bailey et al48 show that IL-1 induces COX-2 in human vessels, with a pattern of prostanoid release of PGE2>PGI2>TXB2. The formation of PGE2 is mediated primarily by IL-1ß–induced COX-2 in SMCs and macrophages.21 22 In the present study, protective PGI2 is released predominantly in IL-1ß–stimulated control SMCs. The release of PGI2 may represent an endogenous defense mechanism against endothelial damage.48 In contrast, the expression of COX-2 protein and subsequent release of PGE2 are significantly up-regulated in IL-1ß–stimulated moyamoya SMCs compared with control SMCs. The conversion of exogenous AA into PGE2 by moyamoya SMCs in the presence of IL-1ß is significantly greater than that by control SMCs but does not differ between SMCs in the absence of IL-1ß. IL-1ß–induced prostanoid production by both HMSMC and HCSMC strains is completely blocked by the addition of NS-398 (1 µmol/L), a COX-2–selective inhibitor. Our findings strongly suggest that inflammatory stimuli and the subsequent inflammatory cell response stimulate the overproduction of PGE2 through an IL-1–induced COX-2 pathway in SMCs in moyamoya disease.

PGs of the E series are thought to modulate vasodilation and vascular permeability.18 49 50 51 The excessive amounts of PGE2 released from moyamoya arterial SMCs through COX-2 activation by inflammatory stimuli may increase vascular permeability and decrease vascular tone, facilitating exposure of the vessels to blood constituents, including growth factors and cytokines that might induce and promote the development of intimal thickening in moyamoya disease. The excessive amounts of PGE2 also inhibit the migration and proliferation of SMCs that might be necessary for the rapid repair of vascular wall injury, resulting in the continued increase in vascular permeability and facilitating the prolonged exposure of the vessels to blood constituents. The continued increase in vascular permeability may be much more important in neointimal accumulation than the exposure to excess individual growth factors.52 In addition, PGE2 and IL-1 are potent stimulators of angiogenesis,53 54 55 and they induce the expression of vascular endothelial cell growth factor, which stimulates both angiogenesis and vascular permeability.56 57 The induction of vascular endothelial cell growth factor by PGE2 and IL-1 may be an important mechanism in inflammatory angiogenesis.56 PGE2 and IL-1 may directly or indirectly play an important role in angiogenesis in moyamoya disease.

The mechanism of the specific response of moyamoya SMCs to IL-1ß is presently unknown. The distinct increase in PGE2, but not NO, production in moyamoya SMCs may indicate altered intracellular signaling pathways by which IL-1 induces NO and PG synthesis. Recent findings demonstrate that COX-2–selective inhibitors have excellent anti-inflammatory properties.17 Our findings suggest a possible interaction between the immune system and the vessel wall in moyamoya disease and serve as a basis for the clinical use of nonsteroidal anti-inflammatory drugs in the treatment of moyamoya disease.


*    Acknowledgments
 
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan. We thank Dr Margaret Dooley Ohto for reviewing the manuscript. We thank Naofumi Yamamoto (Nippon Medical School) for technical support on enzyme immunoassay.

Received July 12, 1999; accepted September 1, 1999.


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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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