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(Journal of Leukocyte Biology. 2000;68:423-428.)
© 2000 by Society for Leukocyte Biology

Induction of cyclooxygenase-2 expression during HIV-1-infected monocyte-derived macrophage and human brain microvascular endothelial cell interactions

Cândida F. Pereira, Leonie A. Boven, Jeena Middel, Jan Verhoef and Hans S. L. M. Nottet

Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, University Medical Center, Utrecht, The Netherlands

Correspondence: Cândida da Fonseca Pereira, Eijkman-Winkler Institute, Section Neuroimmunology, UMC, hp G04.614, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands. E-mail: C.F.Pereira{at}lab.azu.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD) is a neurodegenerative disease characterized by HIV infection and replication in brain tissue. HIV-1-infected monocytes overexpress inflammatory molecules that facilitate their entry into the brain. Prostanoids are lipid mediators of inflammation that result from cyclooxygenase-2 (COX-2) activity. Because COX-2 is normally induced during inflammatory processes, the aim of this study was to investigate whether COX-2 expression is up-regulated during monocyte-brain endothelium interactions. In vitro cocultures of HIV-infected macrophages and brain endothelium showed an up-regulation of COX-2 expression by both cell types. This up-regulation occurs via an interleukin-1ß (IL-1ß)-dependent mechanism in macrophages and via an IL-1ß-independent mechanism in endothelial cells. Thus, interactions between HIV-infected monocytes and brain endothelium result in COX-2 expression and, as such, might contribute to the neuropathogenesis of HIV infection.

Key Words: HIV-1-associated dementia • cytokines • eicosanoids • in vitro cocultures • reverse transcriptase-polymerase chain reaction • Western blot


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Human immunodeficiency virus type-1 (HIV-1) -associated dementia (HAD) occurs in approximately one-third of adults and one-half of children with AIDS and is characterized by progressive motor and cognitive loss. The most severe neurological complication of this disease is HIV encephalitis that is characterized by neuronal damage and loss, multinucleated giant cell formation, microglial nodes, astrocytosis, myelin pallor, and infiltration of monocytic cells into brain parenchyma [1 , 2 ]. HIV entry and monocyte migration into the brain are key events in HAD [2 , 3 ]. Selective induction of adhesion molecules by HIV-infected monocytes was indicated as a possible mechanism for the transendothelial migration of HIV-infected monocytes into the brain [4 ]. Also, CC chemokines, cytokines capable of attracting monocytes/macrophages to sites of inflammation, have been found to be elevated in the brains of demented AIDS patients [5 , 6 ]. Blood-derived monocytes that infiltrate into the brain during HIV-1 infection were shown to be immune-activated and to express proinflammatory cytokines like interleukin-1ß (IL-1ß) and tumor necrosis factor {alpha} (TNF-{alpha}) [7 , 8 ]. These cytokines are known to induce nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), enzymes that produce nitric oxide (NO) and prostanoids, respectively [9 10 11 12 13 ].

In this study, the role of COX-2 in the neuropathogenesis of HIV infection was investigated. COX-2 is the inducible isoform of COX, which is the enzyme responsible for the conversion of arachidonic acid into prostanoids: prostaglandins and thromboxanes. COX-2 expression can be induced in inflammatory cells and in the central nervous system after stimulation with proinflammatory cytokines, platelet-activating factor (PAF), and also HIV-1 gp120 [12 , 14 , 15 ]. COX-2 cytotoxicity mechanisms may be related to production of reactive oxygen species (ROS), production of prostanoids, or induction of apoptosis via prostaglandin E2 (PGE2) [11 , 16 ]. Within the brain, COX-2 expression was shown to be induced in neurons [17 , 18 ], astrocytes [10 ], brain endothelial cells [13 , 19 ], monocytes/macrophages [14 ], and microglia [20 ]. Increased levels of COX-2 were found to be associated with several neurological diseases such as Alzheimer’s disease [21 ], ischemia [16 ], acute systemic experimental inflammation [22 ], experimental fever [13 ], and infarct [23 ]. In addition, some studies showed that non-steroidal anti-inflammatory drugs (NSAIDs) could ameliorate disease progression in Alzheimer’s disease and ischemia [16 , 21 ].

Several studies have already attempted to correlate COX-2 with HAD. Prostaglandin levels were found to be elevated in cerebrospinal fluid (CSF) of HIV-demented patients [24 ]. Genis and colleagues showed that HIV neuropathogenesis is mediated, in part, through cytokines and arachidonic acid metabolites produced during cell-cell interactions between HIV-infected brain macrophages and astrocytes [25 ]. HIV gp120 was shown to induce apoptosis via enhancement of COX-2 expression in rat neocortex [15 ]. Some preliminary data demonstrated COX-2 expression in perivascular areas of brain tissue from demented AIDS patients [26 ]. Still, there is no information concerning COX-2 expression during monocyte transendothelial migration into the brain. Therefore, the aim of this study was to investigate whether COX-2 expression was induced during monocyte-brain endothelium interactions.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Isolation and culture of primary human monocytes and brain microvascular endothelial cells (BMVEC)
Peripheral blood mononuclear cells were isolated from heparinized blood from HIV-1-, HIV-2-, and hepatitis B-seronegative donors and obtained on Ficoll-Hypaque density gradients. Cells were washed twice and monocytes were purified by countercurrent centrifugal elutriation. Cells were >98% monocytes by criteria of cell morphology on May-Grünwald-Giemsa-stained cytosmears and by nonspecific esterase staining using {alpha}-naphthylacetate (Sigma, St. Louis, MO) as substrate. Monocytes were cultured in suspension at a concentration of 2 x 106 cells/mL in Teflon flasks (Nalgene, Rochester, NY) in Dulbecco’s modified Eagle’s medium (DMEM) with 10% heat-inactivated human AB serum negative for anti-HIV antibodies, 10 µg/mL gentamicin, and 10 µg/mL ciprofloxacin (Sigma). As previously described, HIV-1 infection of nonadherent macrophages, especially when using a low multiplicity of infection, appears much more reproducible than infection of macrophages that were first allowed to adhere [27 ].

Human BMVEC were obtained from Cell Systems (Kirkland, WA) and propagated as adherent monolayers on highly purified type 1 collagen-coated T-75 tissue culture flasks (Costar, Cambridge, MA) [4 ].

Cocultivation of HIV-1-infected macrophages and BMVEC
After 7 days monocyte-derived macrophages (MDM) were recovered from the Teflon flasks and infected with HIV-1Ba-L (strain titered in MDM) at a multiplicity of infection of 0.01 for 2 h. HIV-infected and mock-infected MDM were washed twice to remove unbound virus and cultured in Teflon flasks for an additional 5 days to establish a chronic infection. Then, MDM were washed and added directly or in a chamber insert (trans-well) to 24-well plates containing a monolayer of BMVEC at a 1:1 ratio. For the IL-1ß blocking experiments, 5 µg/mL anti-human IL-1ß polyclonal goat antibody (R & D Systems, Minneapolis, MN) was added. At different time points cells were lysed for RNA isolation.

RT-PCR detection of COX-2 mRNA
Cocultures of MDM and BMVEC were homogenized and lysed in 1 mL TRIzol (Life Technologies, Gaithersburg, MD) according to the manufacturer’s guidelines. Total RNA was dissolved in diethylpyrocarbonate (DEPC)-treated water, 1 µg of RNA was used for the synthesis of complementary DNA, and PCR reactions were performed as described previously [27 ]. COX-2 primers were 5’-TTCAAATGAGATTGTGGGAAAATTGCT-3’ (sense) and 5’-AGATCATCTCTGCCTGAGTATCTT-3’ (antisense). GAPDH primers were 5’-CCATGGAGAAGGCTGGGG-3’ (sense) and 5’-CAAAGTTGTCATGGATGACC-3’ (antisense). For semi-quantification every primer pair was tested at different cycle numbers to determine the linear range. GAPDH mRNA levels were measured at 23 cycles, whereas cDNA had to be subjected to 37 cycles to detect COX-2 mRNA. Aliquots of 5 µL of the biotinylated PCR product were semi-quantitatively analyzed using a fluorescent digoxigenin detection enzyme-linked immunosorbent assay (ELISA) kit (Boehringer Mannheim) according to the manufacturer’s protocol as described previously [27 ]. The digoxigenin-labeled probe for COX-2 was 5’-GTTTGCATTCTTTGCCCAGC-3’ and for GAPDH was 5’-CTGCACCACCAACTGCTTAGC-3’. All data were normalized against GAPDH mRNA levels, which was used as an internal standard. COX-2 mRNA expression levels were expressed as relative fluorescence units (RFU).

Detection of COX-2 protein by Western blot
Samples were collected with TRIzol (Life Technologies) according to the manufacturer’s guidelines. Proteins were isolated as described previously [28 ]. Total protein amount was determined by the method of Bradford [29 ]. Samples were diluted in gel-loading buffer [125 mM Tris-HCl, 1% sodium dodecyl sulfate (SDS), 20% glycerol, 0.005% bromophenol blue, and 4% ß-mercaptoethanol] to a final concentration of 125 µg/mL and boiled for 10 min. Solubilized proteins were fractionated in an SDS-polyacrylamide gel electrophoresis (10% gradient gel) and transferred to a nitrocellulose membrane. The immunoblot was washed with phosphate-buffered saline (PBS)-0.1% Tween-20 and incubated with primary antibody (anti-COX-2 polyclonal goat antibody specific for human, rat, and mouse COX-2, Santa Cruz Biotechnology, Santa Cruz, CA) diluted 1:200 in PBS/bovine serum albumin (BSA)/azide, for 1 h at room temperature (RT). Afterwards the immunoblot was washed with PBS-0.1% Tween-20 and incubated with peroxidase-labeled conjugate (rabbit anti-goat, DAKO, Denmark) diluted 1:1000 in PBS, for 1 h at RT. Finally, the immunoblot was washed with PBS-0.1% Tween-20, colored with 3,3-diaminobenzidine-tetrahydrochloride, and washed with tap water.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
COX-2 mRNA levels are up-regulated in cocultures allowing cell-cell contact between BMVEC and HIV-1-infected or uninfected macrophages
Because COX-2 is expressed mainly in perivascular areas of brain tissue from AIDS patients with HAD and monocytic cell infiltration is a common feature in HAD [26 ], the effect of the interactions between MDM and BMVEC on COX-2 production was investigated in vitro. BMVEC, HIV-infected, and uninfected MDM were cultured separately and cocultures of BMVEC and HIV-infected or uninfected MDM were performed. Results are depicted in Figure 1 . COX-2 mRNA expression levels increased in cocultures of uninfected or HIV-infected MDM and BMVEC compared with all other culture conditions (P < 0.05 according to Student’s t test). The RFU for cocultures of uninfected or HIV-infected MDM and BMVEC were 131 ± 21 and 261 ± 32, respectively. The RFU for BMVEC, uninfected MDM, and HIV-infected MDM were 80 ± 16, 47 ± 6, and 70 ± 27, respectively. Cocultures of HIV-infected MDM and BMVEC expressed the highest levels of COX-2 mRNA.



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  		Figure 1. COX-2 mRNA expression by BMVEC (E), uninfected MDM (m), HIV-infected MDM (Hm), and in cocultures between BMVEC and uninfected MDM (E + m) and BMVEC and HIV-infected MDM (E + Hm). Cocultures allowed cell-cell contact. mRNA levels are expressed as relative fluorescence units (RFU). Results are representative of at least three independent experiments, and individual samples were analyzed three times by semi-quantitative PCR. *P < 0.05 (according to Student’s t test).

 
Soluble factors produced by HIV-1-infected macrophages are responsible for the induction of COX-2 mRNA expression in BMVEC
To determine whether soluble factors produced by MDM had any effect on COX-2 expression by BMVEC, cocultures of MDM and BMVEC were performed with the use of a trans-well system. Uninfected or HIV-infected MDM were cultured in a chamber insert with BMVEC in the lower compartment. This coculture system did not allow any cell-cell contact. mRNA was isolated from BMVEC cultivated alone or in the trans-well system and RT-PCR was performed (Fig. 2 ). When BMVEC were cocultured with uninfected MDM there was no significant up-regulation of COX-2 expression when compared to BMVEC cultivated alone (P > 0.05 according to Student’s t test). When BMVEC were cocultured with HIV-infected MDM there was a twofold increase in COX-2 expression when compared to all other culture conditions (P < 0.05 according to Student’s t test). Thus, soluble factors produced by HIV-infected macrophages cause an increase in COX-2 mRNA expression in BMVEC.



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  		Figure 2. COX-2 mRNA expression by BMVEC (E) and by BMVEC after being cocultured with a chamber insert (trans-well) containing uninfected MDM [E (m tw)] or HIV-infected MDM [E (Hm tw)]. mRNA levels are expressed as relative fluorescence units (RFU). Results are representative of at least three independent experiments and individual samples were analyzed three times by semi-quantitative PCR. *P < 0.05 (according to Student’s t test).

 
Soluble factors produced by BMVEC are responsible for the induction of COX-2 mRNA expression in macrophages
To determine whether soluble factors produced by BMVEC had any effect on COX-2 expression by macrophages, cocultures of MDM and BMVEC were performed using a trans-well system as described in the previous section. mRNA was isolated from uninfected or HIV-1-infected MDM cultured alone or in the trans-well system and RT-PCR was performed. The results are shown in Figure 3 . The RFU for uninfected MDM was 9 ± 4, whereas the RFU for uninfected MDM cultured in the presence of BMVEC was 38 ± 18 (P < 0.05 according to Student’s t test). Also, COX-2 expression by HIV-infected MDM was 42 ± 14 while the RFU for HIV-infected MDM cultured with BMVEC was 97 ± 12 (P < 0.05 according to Student’s t test). This suggests that soluble factors produced by BMVEC cause an increase in COX-2 mRNA expression in macrophages.



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  		Figure 3. COX-2 mRNA expression by uninfected MDM (m) or HIV-infected MDM (Hm) cultured in a chamber insert with BMVEC in the lower compartment [m (E tw) and Hm (E tw), respectively]. mRNA levels are expressed as relative fluorescence units (RFU). Results are representative of at least three independent experiments, and individual samples were analyzed three times by semi-quantitative PCR. *P < 0.05 (according to Student’s t test).

 
COX-2 protein levels are elevated in cocultures of macrophages and BMVEC
COX-2 protein levels in the in vitro cocultures mentioned in the previous sections were determined by Western blot. The results are shown in Figure 4 . Cocultures of BMVEC and uninfected MDM (lane 2) or HIV-infected MDM (lane 3) showed higher COX-2 protein levels than any of these cell types cultivated alone (lanes 1, 8, and 9). COX-2 protein levels in BMVEC were higher when they were cocultured in a trans-well with uninfected MDM or HIV-infected MDM (lanes 4 and 5, respectively). Also, COX-2 protein levels in uninfected MDM and HIV-infected MDM were higher when they were cocultured in a trans-well with BMVEC (lanes 6 and 7, respectively). The Western blot technique is less sensitive than the RT-PCR. For instance, lanes 1, 8, and 9 do not show any COX-2 protein, whereas the same three samples in Figure 1 show low but detectable levels of COX-2 mRNA. Thus, COX-2 mRNA expression and protein levels are correlated.



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  		Figure 4. COX-2 protein levels in BMVEC (lane 1), cocultures between BMVEC and uninfected MDM (lane 2), BMVEC and HIV-infected MDM (lane 3), BMVEC after being cocultured with a chamber insert (trans-well) containing uninfected MDM (lane 4) or HIV-infected MDM (lane 5), uninfected or HIV-infected MDM cultured in a chamber insert with BMVEC in the lower compartment (lanes 6 and 7, respectively), uninfected MDM (lane 8), and HIV-infected MDM (lane 9). Results are representative of at least two independent Western blot experiments.

 
IL-1ß produced by BMVEC induces COX-2 mRNA expression in macrophages
Because some studies implicate IL-1ß as a proinflammatory cytokine capable of inducing COX-2 expression in macrophages and endothelial cells [13 , 30 , 31 ], trans-well coculture experiments were repeated in the presence or absence of a neutralizing antibody against IL-1ß (anti-IL-1ß). COX-2 mRNA expression by BMVEC and MDM was measured by RT-PCR. Addition of anti-IL-1ß resulted in a 1.5-fold decrease in endogenous COX-2 mRNA expression by BMVEC (P < 0.05 according to Student’s t test) but did not decrease COX-2 mRNA expression by BMVEC cocultured with MDM (P > 0.05 according to Student’s t test). The results are shown in Figure 5 . On the other hand, addition of anti-IL-1ß did not affect endogenous COX-2 mRNA expression by MDM (P > 0.05 according to Student’s t test) but resulted in a decrease of COX-2 mRNA expression by fivefold in uninfected MDM and 10-fold in HIV-infected MDM cocultured with BMVEC (P < 0.05 according to Student’s t test). Results are depicted in Figure 6 . IL-1ß mRNA expression in MDM and BMVEC was decreased when anti-IL-1ß antibody was added (data not shown). Addition of an isotype-matched negative control antibody to the cultures did not affect COX-2 mRNA expression (data not shown). These data indicate that COX-2 expression by macrophages is up-regulated by IL-1ß produced by BMVEC, whereas other soluble factor(s) produced by macrophages are responsible for the induction of COX-2 expression by BMVEC.



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  		Figure 5. Effect of anti-IL-1ß on COX-2 mRNA expression by BMVEC (E) and by BMVEC cocultured in a trans-well system (tw) with uninfected MDM [E (m tw)] or HIV-infected MDM [E (Hm tw)], mRNA levels are expressed as relative fluorescence units (RFU). Results are representative of at least three independent experiments and individual samples were analyzed three times by semi-quantitative PCR. *P < 0.05 (according to Student’s t test).

 


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  		Figure 6. Effect of anti-IL-1ß on COX-2 mRNA expression by uninfected MDM (m) or HIV-infected MDM (Hm) and by uninfected MDM cocultured in a trans-well system (tw) with BMVEC [m (E tw)] and in HIV-infected MDM cocultured in a tw with BMVEC [Hm (E tw)]. mRNA levels are expressed as relative fluorescence units (RFU). Results are representative of at least three independent experiments, and individual samples were analyzed three times by semi-quantitative PCR. *P < 0.05 (according to Student’s t test).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because increased COX-2 expression levels are associated with several neuroinflammatory diseases [13 , 16 , 21 22 23 24 25 ], the expression levels of COX-2 were investigated in an in vitro model that mimics some aspects of HIV neuropathogenesis. COX-2 immunoreactivity in brain tissue from demented AIDS patients was mainly detected in perivascular areas with observed cellular infiltration [26 ]. Our in vitro data did show that interactions between macrophages and brain endothelial cells result in increased COX-2 mRNA expression. HIV-1 infection of macrophages resulted in an even higher increase of COX-2 expression. COX-2 up-regulation did not require cell-cell contact and occurred via an IL-1ß-dependent mechanism in macrophages. Some conclusions can be drawn from this study.

First, HIV-1 infection of macrophages potentiates COX-2 expression in cocultures of macrophages and brain endothelial cells. This finding is supported by reports that showed elevated levels of prostaglandins in brains of demented AIDS patients [24 ], inducibility of both prostaglandins and leukotrienes by HIV gp120 [32 ], and enhanced production of leukotrienes by cocultures of HIV-infected macrophages and astrocytes [25 ].

Second, COX-2 expression is up-regulated during macrophage/brain endothelial cell interactions. This suggests that COX-2 might be involved in the massive monocyte transendothelial migration observed in HAD. Some previous studies showed a correlation between increased endothelium permeability, lipid mediators of inflammation, cytokines, and COX-2. Leukotrienes, products of the lipoxygenase pathway of arachidonic acid metabolism, were found to induce blood-brain barrier permeability [33 ] and Bjork and colleagues demonstrated that platelet-activating factor, an inducer of COX-2 expression, can increase microvascular permeability [34 ]. It was also suggested that prostaglandin E2 (PGE2) acting in conjunction with nitric oxide could disrupt the blood-brain barrier in an experimental model of bacterial meningitis [35 ]. IL-1ß and TNF-{alpha} were shown to have the capacity to regulate blood-brain barrier permeability and induce transendothelial migration of lymphocytes [36 37 38 ].

Third, the up-regulation of COX-2 expression occurs via an IL-1ß-dependent mechanism in macrophages and via an IL-1ß-independent mechanism in brain endothelial cells. Cytokine-induced production of inflammatory molecules such as COX-2 is a complex network. Interferon-{gamma} was shown to have both stimulatory [12 , 39 ] and inhibitory [40 ] effects on COX-2 production. IL-1ß and TNF-{alpha} are frequently mentioned as inducers of COX-2 together or in combination with other molecules [10 11 12 13 , 41 42 43 ]. Another study showed that CD40 engagement up-regulates COX-2 expression [44 ]. It is conceivable that not one but a combination of cytokines are responsible for the induction of COX-2 in brain endothelial cells.

In conclusion, we showed that COX-2 expression is up-regulated during interactions between HIV-infected macrophages and brain endothelial cells but whether this is a secondary effect caused by macrophage infiltration and subsequent release of inflammatory products or an essential step in macrophage transendothelial migration remains to be investigated. The full comprehension of these phenomena may prove beneficial for future therapeutic strategies designed to prevent infiltration of monocytic cells into the brain.


   ACKNOWLEDGEMENTS
 
This work was supported by grants from the Training and Mobility of Researchers of the European Commission (ERBFMBICT983314) and the Royal Netherlands Academy of Sciences and Arts. Dr. Hans S. L. M. Nottet is a fellow of the Royal Netherlands Academy of Sciences and Arts and Cândida da Fonseca Pereira is a Marie Curie fellow. The authors wish to thank Gerwin A. Huls for kindly providing COX-2 polyclonal antibody.

Received June 2, 2000; accepted June 2, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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