Peroxisome proliferator-activated receptors (PPARs) have been demonstrated to have a role in immune regulation. In general, they are anti-inflammatory and promote Th2 type responses, and they are associated with the alternative activation of macrophages. Interestingly, helminth infections, such as the schistosome blood flukes that cause schistosomiasis, are characterised by a Th2 response and the accumulation of alternative activated macrophages. This would suggest that at some level, PPARs could have a role in the modulation of the immune response in schistosomiasis. This paper discusses possible areas where PPARs could have a role in this disease. 1. Introduction The peroxisome proliferator-activated receptors (PPARs) are a group within the 48 transcription factors of the nuclear hormone receptor family involved in lipid metabolism and inflammation [1]. To be transcriptionally active, they require hetrodimerisation with the retinoid X receptor (RXR) to which the resulting heterodimers bind with peroxisome proliferator-response elements (PPREs) on DNA after activation by a ligand-to-modulate transcription [2]. The PPREs are located at the 5′ end of the target gene and consist of a repeat sequence—AGGTCA—separated by one nucleotide [3]. The binding to the PPRE is orientated with PPAR at the 5′ end and RXR towards the 3′ end [2]. For transcriptional control to occur, the PPAR/RXR heterodimers have to interact with coactivators or suppressors for stimulation or inhibition of target-gene expression, respectively [2]. The PPARs can also block transcription of other genes by interacting with other transcription factors by non-genomic transrepression, whereby they inhibit transcription by preventing dissociation of corepressors or sequester co-activators needed for binding of the transcription factor to the DNA [4]. There are 3 isoforms of the PPAR receptors, PPARα, PPARβ/δ, and PPARγ [5]. PPARα is expressed in the liver, brown fat, heart, and skeletal muscle which have high levels of fatty acid catabolism, while PPARγ is expressed in adipose tissue, the colon, and in macrophages, it is the major regulator in adipocyte differentiation and is a determinant in insulin sensitivity [3]. PPARβ/δ is ubiquitously expressed and is thought to have a role in metabolic disorders [3]. Polyunsaturated fatty acids and eicosanoids act as natural ligands for these receptors; however, synthetic ligands exist such as fibrates that target PPARα and the thiazolidinediones that target PPARγ [3]. PPARS have been demonstrated to be important in a number of different disease states
References
[1]
M. M. Chan, K. W. Evans, A. R. Moore, and D. Fong, “Peroxisome proliferator-activated receptor (PPAR): balance for survival in parasitic infections,” Journal of Biomedicine & Biotechnology, vol. 2010, Article ID 828951, 2010.
[2]
L. Michalik, J. Auwerx, J. P. Berger et al., “International union of pharmacology. LXI. Peroxisome proliferator-activated receptors,” Pharmacological Reviews, vol. 58, no. 4, pp. 726–741, 2006.
[3]
M. Vázquez-Carrera, T. Coll, E. Barroso et al., “The role of peroxisome proliferator-activated receptor on the inflammatory basis of metabolic disease,” PPAR Research, vol. 2010, Article ID 368467, 2010.
[4]
N. S. Tan, L. Michalik, B. Desvergne, and W. Wahli, “Multiple expression control mechanisms of peroxisome proliferator-activated receptors and their target genes,” Journal of Steroid Biochemistry and Molecular Biology, vol. 93, no. 2–5, pp. 99–105, 2005.
[5]
G. Rizzo and S. Fiorucci, “PPARs and other nuclear receptors in inflammation,” Current Opinion in Pharmacology, vol. 6, no. 4, pp. 421–427, 2006.
[6]
A. Yessoufou and W. Wahli, “Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels,” Swiss Medical Weekly, vol. 140, p. w13071, 2010.
[7]
L. Serghides and K. C. Kain, “Peroxisome proliferator-activated receptor γ-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-α secretion by monocytes/macrophages,” Journal of Immunology, vol. 166, no. 11, pp. 6742–6748, 2001.
[8]
F. Nagajyothi, M. S. Desruisseaux, L. M. Weiss et al., “Chagas disease, adipose tissue and the metabolic syndrome,” Memorias do Instituto Oswaldo Cruz, vol. 104, no. 1, pp. 219–225, 2009.
[9]
A. Gallardo-Soler, C. Gómez-Nieto, M. L. Campo et al., “Arginase I induction by modified lipoproteins in macrophages: a peroxisome proliferator-activated receptor-γ/δ-mediated effect that links lipid metabolism and immunity,” Molecular Endocrinology, vol. 22, no. 6, pp. 1394–1402, 2008.
[10]
C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998.
[11]
J. I. Odegaard, R. R. Ricardo-Gonzalez, M. H. Goforth et al., “Macrophage-specific PPARγ controls alternative activation and improves insulin resistance,” Nature, vol. 447, no. 7148, pp. 1116–1120, 2007.
[12]
S. Dasgupta, A. Roy, M. Jana, D. M. Hartley, and K. Pahan, “Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-α,” Molecular Pharmacology, vol. 72, no. 4, pp. 934–946, 2007.
[13]
J. P. Hewitson, J. R. Grainger, and R. M. Maizels, “Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity,” Molecular and Biochemical Parasitology, vol. 167, no. 1, pp. 1–11, 2009.
[14]
L. Chitsulo, D. Engels, A. Montresor, and L. Savioli, “The global status of schistosomiasis and its control,” Acta Tropica, vol. 77, no. 1, pp. 41–51, 2000.
[15]
A. G. P. Ross, P. B. Bartley, A. C. Sleigh et al., “Schistosomiasis,” New England Journal of Medicine, vol. 346, no. 16, pp. 1212–1220, 2002.
[16]
M. L. Burke, M. K. Jones, G. N. Gobert, Y. S. Li, M. K. Ellis, and D. P. McManus, “Immunopathogenesis of human schistosomiasis,” Parasite Immunology, vol. 31, no. 4, pp. 163–176, 2009.
[17]
P. G. Thomas and D. A. Harn Jr., “Immune biasing by helminth glycans,” Cellular Microbiology, vol. 6, no. 1, pp. 13–22, 2004.
[18]
E. J. Pearce and A. S. MacDonald, “The immunobiology of schistosomiasis,” Nature Reviews Immunology, vol. 2, no. 7, pp. 499–511, 2002.
[19]
A. R. de Jesus, A. Magalh？es, D. Gonzalez Miranda et al., “Association of type 2 cytokines with hepatic fibrosis in human Schistosoma mansoni infection,” Infection and Immunity, vol. 72, no. 6, pp. 3391–3397, 2004.
[20]
E. J. Pearce, “Priming of the immune response by schistosome eggs,” Parasite Immunology, vol. 27, no. 7-8, pp. 265–270, 2005.
[21]
D. R. Herbert, C. H？lscher, M. Mohrs et al., “Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology,” Immunity, vol. 20, no. 5, pp. 623–635, 2004.
[22]
G. Schramm, F. H. Falcone, A. Gronow et al., “Molecular characterization of an interleukin-4-inducing factor from Schistosoma mansoni eggs,” Journal of Biological Chemistry, vol. 278, no. 20, pp. 18384–18392, 2003.
[23]
B. Everts, G. Perona-Wright, H. H. Smits et al., “Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses,” Journal of Experimental Medicine, vol. 206, no. 8, pp. 1673–1680, 2009.
[24]
C. Faveeuw, T. Mallevaey, K. Paschinger et al., “Schistosome N-glycans containing core α3-fucose and core β2-xylose epitopes are strong inducers of Th2 responses in mice,” European Journal of Immunology, vol. 33, no. 5, pp. 1271–1281, 2003.
[25]
W. Arozal, K. Watanabe, P. T. Veeraveedu et al., “Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR- agonist actions,” Toxicology, vol. 279, no. 1–3, pp. 91–99, 2011.
[26]
K. Chang, S. A. Francis, E. Aikawa et al., “Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: novel detection by dual-target fluorescence molecular imaging,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 10, pp. 1933–1939, 2010.
[27]
Y.-H. Lee, N.-H. Lee, G. Bhattarai et al., “PPAR inhibits inflammatory reaction in oxidative stress induced human diploid fibloblast,” Cell Biochemistry and Function, vol. 28, no. 6, pp. 490–496, 2010.
[28]
P. E. Polak, S. Kalinin, C. Dello Russo et al., “Protective effects of a peroxisome proliferator-activated receptor-β/δ agonist in experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 168, no. 1-2, pp. 65–75, 2005.
[29]
P. Delerive, K. de Bosscher, S. Besnard et al., “Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1,” Journal of Biological Chemistry, vol. 274, no. 45, pp. 32048–32054, 1999.
[30]
J. D. Ji, H. J. Kim, Y. H. Rho et al., “Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Δ12,14-prostaglandin J2,” Rheumatology, vol. 44, no. 8, pp. 983–988, 2005.
[31]
J. T. Huang, J. S. Welch, M. Ricote et al., “Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase,” Nature, vol. 400, no. 6742, pp. 378–382, 1999.
[32]
M. D. Carter, S. Reese Harry, and D. W. Wright, “Identification of hydroxyeicosatetraenoic acid components of schistosomal hemozoin,” Biochemical and Biophysical Research Communications, vol. 363, no. 3, pp. 867–872, 2007.
[33]
J. L. Reyes and L. I. Terrazas, “The divergent roles of alternatively activated macrophages in helminthic infections,” Parasite Immunology, vol. 29, no. 12, pp. 609–619, 2007.
[34]
T. Kreider, R. M. Anthony, J. F. Urban Jr., and W. C. Gause, “Alternatively activated macrophages in helminth infections,” Current Opinion in Immunology, vol. 19, no. 4, pp. 448–453, 2007.
[35]
W. No？l, G. Raes, G. H. Ghassabeh, P. de Baetselier, and A. Beschin, “Alternatively activated macrophages during parasite infections,” Trends in Parasitology, vol. 20, no. 3, pp. 126–133, 2004.
[36]
P. Loke, A. S. MacDonald, and J. E. Allen, “Antigen-presenting cells recruited by Brugia malayi induce Th2 differentiation of naive CD4+ T cells,” European Journal of Immunology, vol. 30, no. 4, pp. 1127–1135, 2000.
[37]
P. N. Loke, A. S. MacDonald, A. Robb, R. M. Maizels, and J. E. Allen, “Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact,” European Journal of Immunology, vol. 30, no. 9, pp. 2669–2678, 2000.
[38]
R. M. Anthony, J. F. Urban, F. Alem et al., “Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites,” Nature Medicine, vol. 12, no. 8, pp. 955–960, 2006.
[39]
N. Mejri and B. Gottstein, “Intraperitoneal Echinococcus multilocularis infection in C57BL/6 mice affects CD40 and B7 costimulator expression on peritoneal macrophages and impairs peritoneal T cell activation,” Parasite Immunology, vol. 28, no. 8, pp. 373–385, 2006.
[40]
L. I. Terrazas, D. Montero, C. A. Terrazas, J. L. Reyes, and M. Rodríguez-Sosa, “Role of the programmed Death-1 pathway in the suppressive activity of alternatively activated macrophages in experimental cysticercosis,” International Journal for Parasitology, vol. 35, no. 13, pp. 1349–1358, 2005.
[41]
P. Smith, C. M. Walsh, N. E. Mangan et al., “Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages,” Journal of Immunology, vol. 173, no. 2, pp. 1240–1248, 2004.
[42]
S. L. Friedman, “Hepatic fibrosis—overview,” Toxicology, vol. 254, no. 3, pp. 120–129, 2008.
[43]
S. L. Friedman, “Liver fibrosis—from bench to bedside,” Journal of Hepatology, vol. 38, supplement 1, pp. S38–S53, 2003.
[44]
S. L. Friedman, “Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury,” Journal of Biological Chemistry, vol. 275, no. 4, pp. 2247–2250, 2000.
[45]
H. She, S. Xiong, S. Hazra, and H. Tsukamoto, “Adipogenic transcriptional regulation of hepatic stellate cells,” Journal of Biological Chemistry, vol. 280, no. 6, pp. 4959–4967, 2005.
[46]
J. T. M. Tan, S. V. McLennan, W. W. Song et al., “Connective tissue growth factor inhibits adipocyte differentiation,” American Journal of Physiology, vol. 295, no. 3, pp. C740–C751, 2008.
[47]
S. Hazra, S. Xiong, J. Wang, R. A. Rippe, V. K. K. Chatterjee, and H. Tsukamoto, “Peroxisome proliferator-activated receptor γ induces a phenotypic switch from activated to quiescent hepatic stellate cells,” Journal of Biological Chemistry, vol. 279, no. 12, pp. 11392–11401, 2004.
[48]
B. Anthony, J. T. Allen, Y. S. Li, and D. P. McManus, “Hepatic stellate cells and parasite-induced liver fibrosis,” Parasites and Vectors, vol. 3, no. 1, article 60, 2010.
[49]
P. B. Bartley, G. A. Ramm, M. K. Jones, R. G. Ruddell, Y. Li, and D. P. McManus, “A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis,” International Journal for Parasitology, vol. 36, no. 9, pp. 993–1001, 2006.
[50]
D. Chang, L. N. Z. Ramalho, F. S. Ramalho, A. L. C. Martinelli, and S. Zucoloto, “Hepatic stellate cells in human schistosomiasis mansoni: a comparative immunohistochemical study with liver cirrhosis,” Acta Tropica, vol. 97, no. 3, pp. 318–323, 2006.
[51]
H. Chen, Y. W. He, W. Q. Liu, and J. H. Zhang, “Rosiglitazone prevents murine hepatic fibrosis induced by Schistosoma japonicum,” World Journal of Gastroenterology, vol. 14, no. 18, pp. 2905–2911, 2008.
[52]
B. Anthony, W. Mathieson, W. de Castro-Borges, and J. Allen, “Schistosoma mansoni: egg-induced downregulation of hepatic stellate cell activation and fibrogenesis,” Experimental Parasitology, vol. 124, no. 4, pp. 409–420, 2010.
[53]
T. A. Wynn, “Fibrotic disease and the TH1/TH2 paradigm,” Nature Reviews Immunology, vol. 4, no. 8, pp. 583–594, 2004.
