Molecular Characteristics and Potent Immunomodulatory Activity of Fasciola hepatica Cystatin
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Cystatin, a cysteine protease inhibitor found in many parasites, plays important roles in immune evasion. This study analyzed the molecular characteristics of a cystatin from Fasciola hepatica (FhCystatin) and expressed recombinant FhCystatin (rFhcystatin) to investigate the immune modulatory effects on lipopolysaccharide-induced proliferation, migration, cytokine secretion, nitric oxide (NO) production, and apoptosis in mouse macrophages. The FhCystatin gene encoded 116 amino acids and contained a conserved cystatin-like domain. rFhCystatin significantly inhibited the activity of cathepsin B. rFhCystatin bound to the surface of mouse RAW264.7 cells, significantly inhibited cell proliferation and promoted apoptosis. Moreover, rFhCystatin inhibited the expression of cellular nitric oxide, interleukin-6, and tumor necrosis factor-α, and promoted the expression of transforming growth factor-β and interleukin-10. These results showed that FhCystatin played an important role in regulating the activity of mouse macrophages. Our findings provide new insights into mechanisms underlying the immune evasion and contribute to the exploration of potential targets for the development of new drug to control F. hepatica infection.
Abstract
Cystatin, a cysteine protease inhibitor found in many parasites, plays important roles in immune evasion. This study analyzed the molecular characteristics of a cystatin from Fasciola hepatica (FhCystatin) and expressed recombinant FhCystatin (rFhcystatin) to investigate the immune modulatory effects on lipopolysaccharide-induced proliferation, migration, cytokine secretion, nitric oxide (NO) production, and apoptosis in mouse macrophages. The FhCystatin gene encoded 116 amino acids and contained a conserved cystatin-like domain. rFhCystatin significantly inhibited the activity of cathepsin B. rFhCystatin bound to the surface of mouse RAW264.7 cells, significantly inhibited cell proliferation and promoted apoptosis. Moreover, rFhCystatin inhibited the expression of cellular nitric oxide, interleukin-6, and tumor necrosis factor-α, and promoted the expression of transforming growth factor-β and interleukin-10. These results showed that FhCystatin played an important role in regulating the activity of mouse macrophages. Our findings provide new insights into mechanisms underlying the immune evasion and contribute to the exploration of potential targets for the development of new drug to control F. hepatica infection.
참고문헌 (33)
- Stella Mazeri, "Estimation of the impact of Fasciola hepatica infection on time taken for UK beef cattle to reach slaughter weight", Scientific Reports, 7(1), pp.7319~ (2017), Springer Science and Business Media LLC[DOI]
- N. J. Beesley, "Fasciola and fasciolosis in ruminants in Europe: Identifying research needs", Transboundary and Emerging Diseases, 65, pp.199~216 (2017), Hindawi Limited[DOI]
- S. Mas-Coma, "Human fascioliasis infection sources, their diversity, incidence factors, analytical methods and prevention measures – CORRIGENDUM", Parasitology, 147(5), pp.601~601 (2020), Cambridge University Press (CUP)[DOI]
- Monica Catarina Botelho, "Commentary: Human Liver Flukes", Frontiers in Public Health, 30(6), pp.122~ (2018), Frontiers Media SA[DOI]
- Mark W. Robinson, "Fasciola hepatica: The therapeutic potential of a worm secretome", International Journal for Parasitology, 43(3-4), pp.283~291 (2013), Elsevier BV[DOI]
- James R. Jefferies, "Proteomic analysis ofFasciola hepatica excretory-secretory products", PROTEOMICS, 1(8), pp.1128~1132 (2001), Wiley[DOI]
- Ernesto Rodríguez, "Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal", GalNAc Lectin, 2017, pp.8, 264~[DOI]
- Rick M. Maizels, "Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules", Immunity, 49(5), pp.801~818 (2018), Elsevier BV[DOI]
- Mark W. Robinson, "A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides", PLoS Pathogens, 7(5), pp.e1002042~ (2011), Public Library of Science (PLoS)[DOI]
- Magnus Abrahamson, "Cystatins", Biochemical Society Symposia, 70, pp.179~199 (2003), Portland Press Ltd.[DOI]
- Janice Murray, "Bm-CPI-2, a cystatin from Brugia malayi nematode parasites, differs from Caenorhabditis elegans cystatins in a specific site mediating inhibition of the antigen-processing enzyme AEP", Molecular and Biochemical Parasitology, 139(2), pp.197~203 (2005), Elsevier BV[DOI]
- MARTÍN CANCELA, "Functional characterization of single-domain cystatin-like cysteine proteinase inhibitors expressed by the trematode<i>Fasciola hepatica<", i>, 2017, pp.144(13), 1695~1707[DOI]
- Ai-Ling Tian, "A recombinant Fasciola gigantica 14-3-3 epsilon protein (rFg14-3-3e) modulates various functions of goat peripheral blood mononuclear cells", Parasites & Vectors, 11(1), pp.152~ (2018), Springer Science and Business Media LLC[DOI]
- Nawal M. Boukli, "Fasciola hepatica and Schistosoma mansoni: Identification of Common Proteins by Comparative Proteomic Analysis", Journal of Parasitology, 97(5), pp.852~861 (2011), American Society of Parasitologists[DOI]
- D. P. McMANUS, "Vaccines against the zoonotic trematodes<i>Schistosoma japonicum<", i>,<i>Fasciola hepatica<, i>, pp.Parasitology, 2006[DOI]
- Qing Liu, "Proteomic analysis of Fasciola hepatica excretory and secretory products (FhESPs) involved in interacting with host PBMCs and cytokines by shotgun LC-MS", MS, 2016, pp.116(2), 627~635[DOI]
- Xiao Yang, "Cloning, expression and characterisation of a type II cystatin from Schistosoma japonicum, which could regulate macrophage activation", Parasitology Research, 113(11), pp.3985~3992 (2014), Springer Science and Business Media LLC[DOI]
- Peter E. Kima, "The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist", International Journal for Parasitology, 37(10), pp.1087~1096 (2007), Elsevier BV[DOI]
- Adam F. Sander, "DNA secondary structures are associated with recombination in major<i>Plasmodium falciparum<", i>variable surface antigen gene families, 2013, pp.42(4), 2270~2281[DOI]
- Christian Klotz, "Cystatins of Parasitic Organisms", Advances in Experimental Medicine and Biology, 712, pp.208~221 (2011), Springer US[DOI]
- Yujian Wang, "Characterization of a secreted cystatin of the parasitic nematode Haemonchus contortus and its immune-modulatory effect on goat monocytes", Parasites & Vectors, 10(1), pp.425~ (2017), Springer Science and Business Media LLC[DOI]
- Terry Y. Nakagawa, "The role of lysosomal proteinases in MHC class Il-mediated antigen processing and presentation", Immunological Reviews, 172(1), pp.121~129 (1999), Wiley[DOI]
- Lin Chen, "Cysteine protease inhibitor of Schistosoma japonicum - A parasite-derived negative immunoregulatory factor", Parasitology Research, 116(3), pp.901~908 (2017), Springer Science and Business Media LLC[DOI]
- Behrendt P, "A helminth protease inhibitor modulates the lipopolysaccharide-induced proinflammatory phenotype of microglia in vitro", Neuroimmunomodulation, 23, pp.109~121 (2016)[DOI]
- 장성원, "Parasitic Helminth Cystatin Inhibits DSS-Induced Intestinal Inflammation Via IL-10^+F4", 80^+ Macrophage Recruitment, 2011, pp.49(3), 245~254[DOI]
- Yanxia Sun, "Modulation of dendritic cell function and immune response by cysteine protease inhibitor from murine nematode parasite Heligmosomoides polygyrus", Immunology, 138(4), pp.370~381 (2013), Wiley[DOI]
- Varin A, "Alternative activation of macrophages : immune function and cellular biology", Immunobiology, 214, pp.630~641 (2009)[DOI]
- Laura Cervi, "Fasciola hepatica-Induced Immune Suppression of Spleen Mononuclear Cell Proliferation: Role of Nitric Oxide", Clinical Immunology and Immunopathology, 87(2), pp.145~154 (1998), Elsevier BV[DOI]
- A. Escamilla, "Apoptosis of peritoneal leucocytes during early stages of Fasciola hepatica infections in sheep", Veterinary Parasitology, 238, pp.49~53 (2017), Elsevier BV[DOI]
- Chen D, "The multitasking Fasciola gigantica Cathepsin B interferes with various functions of goat peripheral blood mononuclear cells in vitro", Front Immunol, 10, pp.1707~ (2019)[DOI]
- Reinhard E. Voll, "Immunosuppressive effects of apoptotic cells", Nature, 390(6658), pp.350~351 (1997), Springer Science and Business Media LLC[DOI]
- Malgorzata Bzowska, "Increased IL-10 production during spontaneous apoptosis of monocytes", European Journal of Immunology, 32(7), pp.2011~2020 (2002), Wiley[DOI]
- WanJun Chen, "TGF-β Released by Apoptotic T Cells Contributes to an Immunosuppressive Milieu", Immunity, 14(6), pp.715~725 (2001), Elsevier BV[DOI]