Peroxisome Proliferator-Activated Receptor and Retinoid X Receptor Agonists Have Minimal Effects on the Interaction of Endothelial Cells wi
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感染与免疫杂志 2005年第2期
McLaughlin-Rotman Global Health Program, McLaughlin Centre for Molecular Medicine, University of Toronto, and Centre for Travel and Tropical Medicine, Toronto General Hospital, Toronto, Ontario, Canada
ABSTRACT
Peroxisome proliferator-activated receptor -retinoid X receptor (PPAR-RXR) agonists had minimal effects on the surface levels of CD36, intercellular cell adhesion molecule-1, or platelet-endothelial cell adhesion molecule-1 and had no effect on the cytoadherence of infected erythrocytes to either human umbilical vein endothelial cells or human microvascular endothelial cells or on malaria-induced interleukin-6 secretion from these cells. PPAR-RXR agonists do not significantly modify malaria-infected erythrocyte-endothelial cell interactions in vitro.
TEXT
Severe Plasmodium falciparum malaria is associated with high parasite burdens, excessive inflammatory responses to malaria glycosylphosphatidylinositol (GPI) (5, 13), and the sequestration of infected erythrocytes (IEs) in vital organs (9). Many endothelial cell receptors have been implicated in sequestration including CD36, intercellular cell adhesion molecule-1 (ICAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) (6). Almost all IEs adhere to CD36. CD36 is expressed on endothelial cells but also on monocytes/macrophages, where it has been implicated in the innate clearance of IEs (8). These observations suggest that malaria-CD36 interactions may represent coevolutionary adaptations that limit inflammatory responses that are deleterious to both the parasite and the host and have led to the hypothesis that increasing monocytes/macrophage CD36 may result in increased parasite clearance and reduced malaria immunopathology (16). CD36 is transcriptionally regulated by the nuclear receptor peroxisome proliferator-activated receptor -retinoid X receptor (PPAR-RXR) (18). PPAR-RXR agonists have been shown to increase CD36-mediated phagocytosis of IEs (12, 14, 15, 17) and to reduce GPI-induced tumor necrosis factor alpha (TNF-) production (14, 15) and have been proposed as potential therapeutics for malaria. However, before this can be explored it is important to investigate their effects on endothelial cell-parasite interactions. Furthermore, since this class of compounds is in common use, it is important to understand their effects on host-malaria interactions. Here we examine the effects of PPAR-RXR agonists on the expression of CD36, ICAM-1, and PECAM-1, IE cytoadherence, and GPI-induced cytokine response by using human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (MDECs).
We used flow cytometry to examine the effects of 48-h treatment with the PPAR agonist troglitazone and 9-cis-retinoic acid, a vitamin A metabolite and RXR agonist, on the expression of CD36, ICAM-1, and PECAM-1 on HUVECs and MDECs (Clonetics) with the monocytic cell line U937 as a control. PPAR agonists have been shown to increase CD36 expression in monocytic cells (10, 14, 15, 18), while their impact on ICAM-1 expression varies according to cell type (1, 2). 9-cis-Retinoic acid, as expected, significantly increased CD36 levels on U937 cells (Fig. 1A); however, it did not significantly modulate the level of CD36, ICAM-1, or PECAM-1 on either MDECs or HUVECs (Fig. 1 to 3). Troglitazone increased CD36 levels on U937 cells (Fig. 1A) as previously reported (10, 14, 15, 18), but CD36, ICAM-1, and PECAM-1 levels on MDECs were unaffected (Fig. 1 to 3). Although troglitazone did not affect CD36 levels on HUVECs, it did cause a significant increase in both ICAM-1 and PECAM-1 levels (Fig. 1 to 3).
Since severe malaria is associated with elevated levels of TNF- that may upregulate cell adhesion molecules, we also examined concomitant treatment of endothelial cells with PPAR-RXR agonists and TNF-. TNF- did not significantly alter CD36 levels nor the effect of PPAR-RXR agonists in any of the cell types (Fig. 1D to F). TNF- caused an increase in ICAM-1 expression on MDECs, HUVECs, and U937s (Fig. 2D to F) (7). Although troglitazone significantly enhanced ICAM-1 and PECAM-1 expression in TNF--treated MDECs (Fig. 2E and 3C), it inhibited expression in HUVECs (Fig. 2F and 3D). It has been reported that troglitazone has a dual action on ICAM-1 expression in HUVECs (1). In the absence of cytokine stimulation, troglitazone enhanced ICAM-1 expression, while in the presence of TNF-, troglitazone caused a decrease in ICAM-1 (1, 3, 19). Troglitazone has also been shown to inhibit TNF--stimulated vascular cell adhesion molecule-1 and E-selectin in HUVECs (3, 11) but not PECAM-1 as observed here.
We have previously reported that PPAR-RXR agonists enhance monocyte/macrophage uptake of nonopsonized IEs. However, the potential benefits of enhanced clearance may be limited if PPAR-RXR agonists also cause a significant increase in endothelial cell cytoadherence. We investigated the effect of 48-h troglitazone, 9-cis-retinoic acid, or control treatment, with or without concomitant TNF- treatment, on IE cytoadherence to MDECs and HUVECs, as previously described (20). Both MDECs and HUVECs supported the cytoadherence of IEs, although MDECs, which express CD36, did so more avidly. Cytoadherence to control-treated MDECs was significantly inhibited by both CD36 and ICAM-1 antibody blockade (Fig. 4A). Cotreatment with TNF- and 9-cis-retinoic acid or troglitazone did not significantly increase cytoadherence to MDECs.
Cytoadherence to HUVECs was significantly enhanced by troglitazone but not by 9-cis-retinoic acid. Cytoadherence was significantly inhibited only by antibody blockade of ICAM-1 (Fig. 4B). TNF- treatment caused a significant increase in cytoadherence to HUVECs, correlating with the increase seen in ICAM-1 levels.
PPAR-RXR agonists have been shown to have anti-inflammatory properties (4), and we previously demonstrated that they can inhibit GPI-induced TNF- secretion from monocytes (14, 15). We next investigated whether PPAR-RXR agonists modulate endothelial cell-secreted cytokines in response to GPI, as previously described (14, 15).
Lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and malaria GPI induced interleukin-6 (IL-6) production from MDECs and HUVECs, although with differing kinetics (Fig. 5). 9-cis-Retinoic acid decreased PMA-induced IL-6 in both MDECs and HUVECs and LPS-induced IL-6 in HUVECs. Troglitazone caused a small decrease in LPS-induced IL-6 in MDECs and an increase in PMA-induced IL-6 at the early time points in HUVECs. In contrast, GPI-induced IL-6 was unaffected by either 9-cis-retinoic acid or troglitazone treatment of either cell type (Fig. 5C and F). Thus, PPAR-RXR agonists appeared to have little influence on the malaria-stimulated IL-6 response from endothelial cells.
Both troglitazone and 9-cis-retinoic acid have marked effects on monocyte/macrophage-parasite interactions. They significantly increase CD36-mediated IE phagocytosis and cause a significant reduction in malaria-induced TNF- (14, 15). These properties might be expected to have beneficial effects on malaria pathophysiology if they result in enhanced parasite clearance and reduced proinflammatory responses to infection. However, it is important to assess their effects beyond monocytic cells. Our data suggest that PPAR-RXR agonists have minimal effects on endothelial cell-parasite interactions. 9-cis-Retinoic acid does not appear to influence endothelial cell-parasite interactions, including cytoadherence and malaria-induced cytokine production. Troglitazone only has minor effects and these were seen primarily with HUVECs. Although HUVECs are widely used in in vitro studies, their in vivo relevance is unclear, since cytoadherence to these cells is not a component of malaria pathology in vivo. MDECs are a more relevant cell type, and cytoadherence to these cells appears to be unaffected by troglitazone or 9-cis-retinoic acid. This is encouraging, as it implies that PPAR-RXR-mediated enhancement of monocyte/macrophage phagocytosis and modulation of malaria-induced inflammatory responses may not be offset by negatively modulating endothelial cell-parasite interactions. However, an important caveat is that our study did not examine brain endothelium and that additional examination of endothelial cells from a variety of organs may be informative.
ACKNOWLEDGMENTS
This work was supported by the Canadian Institutes of Health Research (CIHR) operating grant MT-13721 (K.C.K.), a Career Scientist Award from the Ontario Ministry of Health (K.C.K.), and a CIHR Canada Research Chair (K.C.K.). Lena Serghides is the recipient of a CIHR postdoctoral research fellowship.
Present address: Department of Immunology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada.
REFERENCES
1. Chen, N. G., and X. Han. 2001. Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium. Biochem. Biophys. Res. Commun. 282:717-722.
2. Clark, R. B. 2002. The role of PPARs in inflammation and immunity. J. Leukoc. Biol. 71:388-400.
3. Cominacini, L., U. Garbin, A. F. Pasini, A. Davoli, M. Campagnola, A. Rigoni, L. Tosetti, and V. Lo Cascio. 1999. The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity. Cell. Adhes. Commun. 7:223-231.
4. Daynes, R. A., and D. C. Jones. 2002. Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2:748-759.
5. Grau, G. E., T. E. Taylor, M. E. Molyneux, J. J. Wirima, P. Vassalli, M. Hommel, and P. H. Lambert. 1989. Tumor necrosis factor and disease severity in children with falciparum malaria. N. Engl. J. Med. 320:1586-1591.
6. Ho, M., and N. J. White. 1999. Molecular mechanisms of cytoadherence in malaria. Am. J. Physiol. 276:C1231-C1242.
7. Ledebur, H. C., and T. P. Parks. 1995. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J. Biol. Chem. 270:933-943.
8. McGilvray, I. D., L. Serghides, A. Kapus, O. D. Rotstein, and K. C. Kain. 2000. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 96:3231-3240.
9. Miller, L. H., D. I. Baruch, K. Marsh, and O. K. Doumbo. 2002. The pathogenic basis of malaria. Nature 415:673-679.
10. Nagy, L., P. Tontonoz, J. G. Alvarez, H. Chen, and R. M. Evans. 1998. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93:229-240.
11. Pasceri, V., H. D. Wu, J. T. Willerson, and E. T. Yeh. 2000. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation 101:235-238.
12. Patel, S. N., L. Serghides, T. G. Smith, M. Febbraio, R. L. Silverstein, T. W. Kurtz, M. Pravenec, and K. C. Kain. 2004. CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages. J. Infect. Dis. 189:204-213.
13. Schofield, L., M. C. Hewitt, K. Evans, M. A. Siomos, and P. H. Seeberger. 2002. Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Nature 418:785-789.
14. Serghides, L., and K. C. Kain. 2001. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages. J. Immunol. 166:6742-6748.
15. Serghides, L., and K. C. Kain. 2002. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet 359:1404-1406.
16. Serghides, L., T. G. Smith, S. N. Patel, and K. C. Kain. 2003. CD36 and malaria: friends or foes Trends Parasitol. 19:461-469.
17. Smith, T. G., L. Serghides, S. N. Patel, M. Febbraio, R. L. Silverstein, and K. C. Kain. 2003. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum. Infect. Immun. 71:393-400.
18. Tontonoz, P., L. Nagy, J. G. Alvarez, V. A. Thomazy, and R. M. Evans. 1998. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252.
19. Wang, N., L. Verna, N. G. Chen, J. Chen, H. Li, B. M. Forman, and M. B. Stemerman. 2002. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J. Biol. Chem. 277:34176-34181.
20. Xiao, L., C. Yang, K. Dorovini-Zis, N. N. Tandon, E. W. Ades, A. A. Lal, and V. Udhayakumar. 1996. Plasmodium falciparum: involvement of additional receptors in the cytoadherence of infected erythrocytes to microvascular endothelial cells. Exp. Parasitol. 84:42-55.(Lena Serghides and Kevin )
ABSTRACT
Peroxisome proliferator-activated receptor -retinoid X receptor (PPAR-RXR) agonists had minimal effects on the surface levels of CD36, intercellular cell adhesion molecule-1, or platelet-endothelial cell adhesion molecule-1 and had no effect on the cytoadherence of infected erythrocytes to either human umbilical vein endothelial cells or human microvascular endothelial cells or on malaria-induced interleukin-6 secretion from these cells. PPAR-RXR agonists do not significantly modify malaria-infected erythrocyte-endothelial cell interactions in vitro.
TEXT
Severe Plasmodium falciparum malaria is associated with high parasite burdens, excessive inflammatory responses to malaria glycosylphosphatidylinositol (GPI) (5, 13), and the sequestration of infected erythrocytes (IEs) in vital organs (9). Many endothelial cell receptors have been implicated in sequestration including CD36, intercellular cell adhesion molecule-1 (ICAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) (6). Almost all IEs adhere to CD36. CD36 is expressed on endothelial cells but also on monocytes/macrophages, where it has been implicated in the innate clearance of IEs (8). These observations suggest that malaria-CD36 interactions may represent coevolutionary adaptations that limit inflammatory responses that are deleterious to both the parasite and the host and have led to the hypothesis that increasing monocytes/macrophage CD36 may result in increased parasite clearance and reduced malaria immunopathology (16). CD36 is transcriptionally regulated by the nuclear receptor peroxisome proliferator-activated receptor -retinoid X receptor (PPAR-RXR) (18). PPAR-RXR agonists have been shown to increase CD36-mediated phagocytosis of IEs (12, 14, 15, 17) and to reduce GPI-induced tumor necrosis factor alpha (TNF-) production (14, 15) and have been proposed as potential therapeutics for malaria. However, before this can be explored it is important to investigate their effects on endothelial cell-parasite interactions. Furthermore, since this class of compounds is in common use, it is important to understand their effects on host-malaria interactions. Here we examine the effects of PPAR-RXR agonists on the expression of CD36, ICAM-1, and PECAM-1, IE cytoadherence, and GPI-induced cytokine response by using human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (MDECs).
We used flow cytometry to examine the effects of 48-h treatment with the PPAR agonist troglitazone and 9-cis-retinoic acid, a vitamin A metabolite and RXR agonist, on the expression of CD36, ICAM-1, and PECAM-1 on HUVECs and MDECs (Clonetics) with the monocytic cell line U937 as a control. PPAR agonists have been shown to increase CD36 expression in monocytic cells (10, 14, 15, 18), while their impact on ICAM-1 expression varies according to cell type (1, 2). 9-cis-Retinoic acid, as expected, significantly increased CD36 levels on U937 cells (Fig. 1A); however, it did not significantly modulate the level of CD36, ICAM-1, or PECAM-1 on either MDECs or HUVECs (Fig. 1 to 3). Troglitazone increased CD36 levels on U937 cells (Fig. 1A) as previously reported (10, 14, 15, 18), but CD36, ICAM-1, and PECAM-1 levels on MDECs were unaffected (Fig. 1 to 3). Although troglitazone did not affect CD36 levels on HUVECs, it did cause a significant increase in both ICAM-1 and PECAM-1 levels (Fig. 1 to 3).
Since severe malaria is associated with elevated levels of TNF- that may upregulate cell adhesion molecules, we also examined concomitant treatment of endothelial cells with PPAR-RXR agonists and TNF-. TNF- did not significantly alter CD36 levels nor the effect of PPAR-RXR agonists in any of the cell types (Fig. 1D to F). TNF- caused an increase in ICAM-1 expression on MDECs, HUVECs, and U937s (Fig. 2D to F) (7). Although troglitazone significantly enhanced ICAM-1 and PECAM-1 expression in TNF--treated MDECs (Fig. 2E and 3C), it inhibited expression in HUVECs (Fig. 2F and 3D). It has been reported that troglitazone has a dual action on ICAM-1 expression in HUVECs (1). In the absence of cytokine stimulation, troglitazone enhanced ICAM-1 expression, while in the presence of TNF-, troglitazone caused a decrease in ICAM-1 (1, 3, 19). Troglitazone has also been shown to inhibit TNF--stimulated vascular cell adhesion molecule-1 and E-selectin in HUVECs (3, 11) but not PECAM-1 as observed here.
We have previously reported that PPAR-RXR agonists enhance monocyte/macrophage uptake of nonopsonized IEs. However, the potential benefits of enhanced clearance may be limited if PPAR-RXR agonists also cause a significant increase in endothelial cell cytoadherence. We investigated the effect of 48-h troglitazone, 9-cis-retinoic acid, or control treatment, with or without concomitant TNF- treatment, on IE cytoadherence to MDECs and HUVECs, as previously described (20). Both MDECs and HUVECs supported the cytoadherence of IEs, although MDECs, which express CD36, did so more avidly. Cytoadherence to control-treated MDECs was significantly inhibited by both CD36 and ICAM-1 antibody blockade (Fig. 4A). Cotreatment with TNF- and 9-cis-retinoic acid or troglitazone did not significantly increase cytoadherence to MDECs.
Cytoadherence to HUVECs was significantly enhanced by troglitazone but not by 9-cis-retinoic acid. Cytoadherence was significantly inhibited only by antibody blockade of ICAM-1 (Fig. 4B). TNF- treatment caused a significant increase in cytoadherence to HUVECs, correlating with the increase seen in ICAM-1 levels.
PPAR-RXR agonists have been shown to have anti-inflammatory properties (4), and we previously demonstrated that they can inhibit GPI-induced TNF- secretion from monocytes (14, 15). We next investigated whether PPAR-RXR agonists modulate endothelial cell-secreted cytokines in response to GPI, as previously described (14, 15).
Lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and malaria GPI induced interleukin-6 (IL-6) production from MDECs and HUVECs, although with differing kinetics (Fig. 5). 9-cis-Retinoic acid decreased PMA-induced IL-6 in both MDECs and HUVECs and LPS-induced IL-6 in HUVECs. Troglitazone caused a small decrease in LPS-induced IL-6 in MDECs and an increase in PMA-induced IL-6 at the early time points in HUVECs. In contrast, GPI-induced IL-6 was unaffected by either 9-cis-retinoic acid or troglitazone treatment of either cell type (Fig. 5C and F). Thus, PPAR-RXR agonists appeared to have little influence on the malaria-stimulated IL-6 response from endothelial cells.
Both troglitazone and 9-cis-retinoic acid have marked effects on monocyte/macrophage-parasite interactions. They significantly increase CD36-mediated IE phagocytosis and cause a significant reduction in malaria-induced TNF- (14, 15). These properties might be expected to have beneficial effects on malaria pathophysiology if they result in enhanced parasite clearance and reduced proinflammatory responses to infection. However, it is important to assess their effects beyond monocytic cells. Our data suggest that PPAR-RXR agonists have minimal effects on endothelial cell-parasite interactions. 9-cis-Retinoic acid does not appear to influence endothelial cell-parasite interactions, including cytoadherence and malaria-induced cytokine production. Troglitazone only has minor effects and these were seen primarily with HUVECs. Although HUVECs are widely used in in vitro studies, their in vivo relevance is unclear, since cytoadherence to these cells is not a component of malaria pathology in vivo. MDECs are a more relevant cell type, and cytoadherence to these cells appears to be unaffected by troglitazone or 9-cis-retinoic acid. This is encouraging, as it implies that PPAR-RXR-mediated enhancement of monocyte/macrophage phagocytosis and modulation of malaria-induced inflammatory responses may not be offset by negatively modulating endothelial cell-parasite interactions. However, an important caveat is that our study did not examine brain endothelium and that additional examination of endothelial cells from a variety of organs may be informative.
ACKNOWLEDGMENTS
This work was supported by the Canadian Institutes of Health Research (CIHR) operating grant MT-13721 (K.C.K.), a Career Scientist Award from the Ontario Ministry of Health (K.C.K.), and a CIHR Canada Research Chair (K.C.K.). Lena Serghides is the recipient of a CIHR postdoctoral research fellowship.
Present address: Department of Immunology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada.
REFERENCES
1. Chen, N. G., and X. Han. 2001. Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium. Biochem. Biophys. Res. Commun. 282:717-722.
2. Clark, R. B. 2002. The role of PPARs in inflammation and immunity. J. Leukoc. Biol. 71:388-400.
3. Cominacini, L., U. Garbin, A. F. Pasini, A. Davoli, M. Campagnola, A. Rigoni, L. Tosetti, and V. Lo Cascio. 1999. The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity. Cell. Adhes. Commun. 7:223-231.
4. Daynes, R. A., and D. C. Jones. 2002. Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2:748-759.
5. Grau, G. E., T. E. Taylor, M. E. Molyneux, J. J. Wirima, P. Vassalli, M. Hommel, and P. H. Lambert. 1989. Tumor necrosis factor and disease severity in children with falciparum malaria. N. Engl. J. Med. 320:1586-1591.
6. Ho, M., and N. J. White. 1999. Molecular mechanisms of cytoadherence in malaria. Am. J. Physiol. 276:C1231-C1242.
7. Ledebur, H. C., and T. P. Parks. 1995. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J. Biol. Chem. 270:933-943.
8. McGilvray, I. D., L. Serghides, A. Kapus, O. D. Rotstein, and K. C. Kain. 2000. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 96:3231-3240.
9. Miller, L. H., D. I. Baruch, K. Marsh, and O. K. Doumbo. 2002. The pathogenic basis of malaria. Nature 415:673-679.
10. Nagy, L., P. Tontonoz, J. G. Alvarez, H. Chen, and R. M. Evans. 1998. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93:229-240.
11. Pasceri, V., H. D. Wu, J. T. Willerson, and E. T. Yeh. 2000. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation 101:235-238.
12. Patel, S. N., L. Serghides, T. G. Smith, M. Febbraio, R. L. Silverstein, T. W. Kurtz, M. Pravenec, and K. C. Kain. 2004. CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages. J. Infect. Dis. 189:204-213.
13. Schofield, L., M. C. Hewitt, K. Evans, M. A. Siomos, and P. H. Seeberger. 2002. Synthetic GPI as a candidate anti-toxic vaccine in a model of malaria. Nature 418:785-789.
14. Serghides, L., and K. C. Kain. 2001. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages. J. Immunol. 166:6742-6748.
15. Serghides, L., and K. C. Kain. 2002. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet 359:1404-1406.
16. Serghides, L., T. G. Smith, S. N. Patel, and K. C. Kain. 2003. CD36 and malaria: friends or foes Trends Parasitol. 19:461-469.
17. Smith, T. G., L. Serghides, S. N. Patel, M. Febbraio, R. L. Silverstein, and K. C. Kain. 2003. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum. Infect. Immun. 71:393-400.
18. Tontonoz, P., L. Nagy, J. G. Alvarez, V. A. Thomazy, and R. M. Evans. 1998. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252.
19. Wang, N., L. Verna, N. G. Chen, J. Chen, H. Li, B. M. Forman, and M. B. Stemerman. 2002. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J. Biol. Chem. 277:34176-34181.
20. Xiao, L., C. Yang, K. Dorovini-Zis, N. N. Tandon, E. W. Ades, A. A. Lal, and V. Udhayakumar. 1996. Plasmodium falciparum: involvement of additional receptors in the cytoadherence of infected erythrocytes to microvascular endothelial cells. Exp. Parasitol. 84:42-55.(Lena Serghides and Kevin )