Abstract
Trichinella spiralis is a zoonotic nematode and food borne parasite and infection with T. spiralis leads to suppression of the host immune response and other immunopathologies. The excretory/secretory (ES) products of T. spiralis play important roles in the process of immunomodulation. However, the mechanisms and related molecules are unknown. Macrophages, a target for immunomodulation by the helminth parasite, play a critical role in initiating and modulating the host immune response to parasite infection. In this study, we examined the effect of ES products from different stages of T. spiralis on modulating J774A.1 macrophage activities. ES products from different stages of T. spiralis reduced the capacity of macrophages to express pro-inflammatory cytokines (tumor necrosis factor α, interleukin-1β , interleukin-6 , and interleukin-12) in response to lipopolysaccharide (LPS) challenge. However, only ES products from 3-day-old adult worms and 5-day-old adult worms/new-born larvae significantly inhibited inducible nitric oxide synthase gene expression in LPS-induced macrophages. In addition, ES products alone boosted the expression of anti-inflammatory cytokines interleukin-10 and transforming growth factor-β and effector molecule arginase 1 in J774A.1 macrophages. Signal transduction studies showed that ES products significantly inhibited nuclear factor-κB translocation into the nucleus and the phosphorylation of both extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase in LPS-stimulated J774A.1 macrophages. These results suggest that ES products regulate host immune response at the macrophage level through inhibition of pro-inflammatory cytokines production and induction of macrophage toward the alternative phenotype, which maybe important for worm survival and host health.
Similar content being viewed by others
References
Gottstein B, Pozio E, Nockler K (2009) Epidemiology, diagnosis, treatment, and control of trichinellosis. Clin Microbiol Rev 22(1):127–145
Jasmer DP (1993) Trichinella spiralis infected skeletal muscle cells arrest in G2/M and cease muscle gene expression. J Cell Biol 121(4):785–793
Bruschi F (2002) The immune response to the parasitic nematode Trichinella and the ways to escape it. From experimental studies to implications for human infection. Curr Drug Targets Immune Endocr Metabol Disord 2(3):269–280
Saunders KA, Raine T, Cooke A, Lawrence CE (2007) Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun 75(1):397–407
Motomura Y, Wang H, Deng Y, El-Sharkawy R, Verdu E, Khan W (2009) Helminth antigen-based strategy to ameliorate inflammation in an experimental model of colitis. Clin Exp Immunol 155(1):88–95
Gruden-Movsesijan A, Ilic N, Mostarica-Stojkovic M, Stosic-Grujicic S, Milic M, Sofronic-Milosavljevic L (2008) Trichinella spiralis: modulation of experimental autoimmune encephalomyelitis in DA rats. Exp Parasitol 118(4):641–647
Park HK, Cho MK, Choi SH, Kim YS, Yu HS (2010) Trichinella spiralis: infection reduces airway allergic inflammation in mice. Exp Parasitol 127(2):539–544
Nagano I, Wu Z, Takahashi Y (2009) Functional genes and proteins of Trichinella spp. Parasitol Res 104(2):197–207
Wing E, Krahenbuhl J, Remington J (1979) Studies of macrophage function during Trichinella spiralis infection in mice. Immunology 36(3):479
Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164(12):6166–6173
Goerdt S, Orfanos CE (1999) Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10(2):137–142
Kreider T, Anthony RM, Urban JF Jr, Gause WC (2007) Alternatively activated macrophages in helminth infections. Curr Opin Immunol 19(4):448–453
Tominaga K, Saito S, Matsuura M, Nakano M (1999) Lipopolysaccharide tolerance in murine peritoneal macrophages induces downregulation of the lipopolysaccharide signal transduction pathway through mitogen-activated protein kinase and nuclear factor-κB cascades, but not lipopolysaccharide-incorporation steps. Biochim Biophys Acta 1450(2):130–144
Hoffmann A, Levchenko A, Scott ML, Baltimore D (2002) The IκB-NF-κB signaling module: temporal control and selective gene activation. Science 298(5596):1241–1245
Lappas M, Permezel M, Georgiou HM, Rice GE (2002) Nuclear factor κB regulation of proinflammatory cytokines in human gestational tissues in vitro. Biol Reprod 67(2):668–673
Hommes D, Peppelenbosch M, Van Deventer S (2003) Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets. Gut 52(1):144–151
Butcher BA, Kim L, Johnson PF, Denkers EY (2001) Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NF-κB. J Immunol 167(4):2193–2201
Dirgahayu P, Fukumoto S, Miura K, Hirai K (2002) Excretory/secretory products from plerocercoids of Spirometra erinaceieuropaei suppress the TNF-α gene expression by reducing phosphorylation of ERK1/2 and p38 MAPK in macrophages. Int J Parasitol 32(9):1155–1162
Gerencer M, Marinculic A, Rapic D, Frankovic M, Valpotic I (1992) Immunosuppression of in vivo and in vitro lymphocyte responses in swine induced by Trichinella spiralis or excretory-secretory antigens of the parasite. Vet Parasitol 44(3–4):263–273
Bruschi F, Carulli G, Azzara A, Homan W, Minnucci S, Rizzuti-Gullaci A, Sbrana S, Angiolini C (2000) Inhibitory Effects of Human Neutrophil Functions by the 45-kD Glycoprotein Derived from the Parasitic Nematode Trichinella spiralis. Int Arch Allergy Immunol 122(1):58–65
Langelaar M, Aranzamendi C, Franssen F, Van der Giessen J, Rutten V, Van der L (2009) Suppression of dendritic cell maturation by Trichinella spiralis excretory/secretory products. Parasite Immunol 31(10):641–645
Ros-Moreno R, Vázquez-López C, Giménez-Pardo C, de Armas-Serra C, Rodríguez F (2000) A study of proteases throughout the life cycle of Trichinella spiralis. Folia Parasitol (Praha) 47(1):49–54
Bian K, Zhong M, Harari Y, Lai M, Weisbrodt N, Murad F (2005) Helminth regulation of host IL-4Ralpha/Stat6 signaling: mechanism underlying NOS-2 inhibition by Trichinella spiralis. Proc Natl Acad Sci USA 102(11):3936–3941
Kenneth J, Thomas D (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25(4):402–408
Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87(1):13–20
Hewitson JP, Grainger JR, Maizels RM (2009) Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol 167(1):1–11
Goodridge HS, Wilson EH, Harnett W, Campbell CC, Harnett MM, Liew FY (2001) Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae. J Immunol 167(2):940–945
Noël W, Raes G, Hassanzadeh Ghassabeh G, De Baetselier P, Beschin A (2004) Alternatively activated macrophages during parasite infections. Trends parasitol 20(3):126–133
Lawrence CE, Paterson JC, Wei XQ, Liew FY, Garside P, Kennedy MW (2000) Nitric oxide mediates intestinal pathology but not immune expulsion during Trichinella spiralis infection in mice. J Immunol 164(8):4229–4243
Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78(6):915–918
Bian K, Harari Y, Zhong M, Lai M, Castro G, Weisbrodt N, Murad F (2001) Down-regulation of inducible nitric-oxide synthase (NOS-2) during parasite-induced gut inflammation: a path to identify a selective NOS-2 inhibitor. Mol Pharmacol 59(4):939–947
Terrazas LI, Walsh KL, Piskorska D, McGuire E, Harn DA Jr (2001) The schistosome oligosaccharide lacto-N-neotetraose expands Gr1 + cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4 + cells: a potential mechanism for immune polarization in helminth infections. J Immunol 167(9):5294–5303
Stephen J (2010) Similarity and diversity in macrophage activation by nematodes, trematodes, and cestodes. J Biomed Biotechnol. doi:10.1155/2010/262609
de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, Johnson K, Kastelein R, Yssel H, De Vries J (1991) Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 174(4):915–924
Beiting DP, Bliss SK, Schlafer DH, Roberts VL, Appleton JA (2004) Interleukin-10 limits local and body cavity inflammation during infection with muscle-stage Trichinella spiralis. Infect Immun 72(6):3129–3137
Beiting DP, Gagliardo LF, Hesse M, Bliss SK, Meskill D, Appleton JA (2007) Coordinated control of immunity to muscle stage Trichinella spiralis by IL-10, regulatory T cells, and TGF-β. J Immunol 178(2):1039–1047
Zhiliang W, Lj SM, Isao N, Yuzo T (2008) Trichinella spiralis: nurse cell formation with emphasis on analogy to muscle cell repair. Parasit Vectors 1(1):27. doi:10.1186/1756-3305-1-27
Reyes J, Terrazas L (2007) The divergent roles of alternatively activated macrophages in helminthic infections. Parasite Immunol 29(12):609–619
P’ng Loke ASMD, Robb A, Maizels RM, Allen JE (2000) Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact. Eur J Immunol 30:2669–2678
Donnelly S, O’Neill SM, Sekiya M, Mulcahy G, Dalton JP (2005) Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages. Infect Immun 73(1):166–173
Chang NCA, Hung SI, Hwa KY, Kato I, Chen JE, Liu CH, Chang AC (2001) A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem 276(20):17497–17506
Dzik J, Go os B, Jagielska E, Zieli ski Z EW-R (2004) A non-classical type of alveolar macrophage response to Trichinella spiralis infection. Parasite Immunol 26(4):197–205
Puneet P, McGrath MA, Tay HK, Al-Riyami L, Rzepecka J, Moochhala SM, Pervaiz S, Harnett MM, Harnett W, Melendez AJ (2011) The helminth product ES-62 protects against septic shock via Toll-like receptor 4-dependent autophagosomal degradation of the adaptor MyD88. Nat Immunol 12(4):344–351
Dirgahayu P, Fukumoto S, Tademoto S, Kina Y, Hirai K (2004) Excretory/secretory products from plerocercoids of Spirometra erinaceieuropaei suppress interleukin-1β gene expression in murine macrophages. Int J Parasitol 34(5):577–584
Wu Z, Nagano I, Asano K, Takahashi Y (2010) Infection of non-encapsulated species of Trichinella ameliorates experimental autoimmune encephalomyelitis involving suppression of Th17 and Th1 response. Parasitol Res 107(5):1173–1188
Acknowledgments
This study was supported by the National S & T Major Program (Grant No. 2008ZX10004-11) and the National Natural Science Foundation of China (Grant No. 30825033, 31030064, 30972177, 30950110328, 81070311 and 31072124), most 2010CB530000 and 2011AA10A200.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xue Bai, Xiuping Wu, Xuelin Wang and Zhenhong Guan contributed equally to this study.
Rights and permissions
About this article
Cite this article
Bai, X., Wu, X., Wang, X. et al. Regulation of cytokine expression in murine macrophages stimulated by excretory/secretory products from Trichinella spiralis in vitro. Mol Cell Biochem 360, 79–88 (2012). https://doi.org/10.1007/s11010-011-1046-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-011-1046-4