Efficacy of Bothrops jararaca venom on the changes in immune functions and TH1/TH2 cytokine balance in murine macrophages
Main Article Content
Abstract
Abstract
Background: Hemorrhage, intravascular coagulation and cardiovascular shock are effects commonly observed in victims bitten by Bothrops snakes. The severity of the envenomation is dependent on the immunological condition of the victim. This study was designed to evaluate the effects of Botrhops jararaca venom on macrophage functions and TH1 / TH2 cytokine balance.
Methods: Various amounts of B. jararaca venom were used, and the activation of macrophages was determined by cytotoxicity assays, hydrogen peroxide production, cell expansion, and phagocytosis. The release of cytokines presents in macrophages treated with B. jararaca venom were measured by ELISA.
Results: The results showed that the Bothrops jararaca venom altered the function of peritoneal macrophage cultures, increasing cytotoxicity and production of H2O2. The venom was able to inhibit cell expansion and phagocytosis. The effects of the venom on immunological mediator production in peritoneal macrophage cultures resulted in an increase in TNF-α, IL-1β and IL-6 production at 24 hours of treatment. The maximum production of NO and IFN-γ were observed at 24–48 and 48-72 hours, respectively. The elevated production of IL-4 and -10 were observed from 24 up to 120 hours after venom exposition.
Conclusion: The combined data suggest that Bothrops jararaca venom has an immunomodulatory immunomodulatory effect for first 24 hours, of venom treatment was observed a balance between TH1 and TH2 cytokines. After this time period with a TH2-dominant response in the TH1/Th2 cytokines.
Keywords: venom, immunomodulator, activation, mediators
Article Details
How to Cite
VALDERRAMA RP, Nuñez et al.
Efficacy of Bothrops jararaca venom on the changes in immune functions and TH1/TH2 cytokine balance in murine macrophages.
Medical Research Archives, [S.l.], v. 4, n. 7, nov. 2016.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/816>. Date accessed: 26 dec. 2024.
Keywords
venom, immunomodulator, activation, mediators
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
5. REFERENCES
1. Aderem A, Underhill DM. (1999). Mechanisms of phagocytosis in macrophages. Annu Rev Immunol, 17:593-623.
2. Aideen B, Denis R. (2001). Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils. The journal of immunology, 168(4):1968-1977.
3. Ande SR, Fussi H, Knauer H, Murkovic M, Ghisla S, Fröhlich KU, Macheroux P. (2008). Induction of apoptosis in yeast by L-amino acid oxidase from the Malayan pit viper Calloselasma rhodostoma. Yeast, 25(5):349–357.
4. Arandjelovic S, Bogic M, Raskovic S. (1998). The role of mononuclear phagocytes and dendritic cells in allergic inflammation. Srp Arh Celok Lek, 126(1-2):46-53.
5. Arruda, MS, Richi VB, Oliveira SM, Vilani-Moreno FR. (2004). Experimental murine mycobareriosis: Evaluation of the functional activity of alveolar macrophages in thalidomide- treated mice. Revista de Biología médica, 37:485-492.
6. Asega AF, Oliveira AK, Menezes MC, Neves-Ferreira AG, Serrano SM. (2014). Interaction of Bothrops jararaca venom metalloproteinases with protein inhibitors. Toxicon, 80:1-8.
7. Auger MJ, Ross JA. The biology of the macrophage. In The Natural Inmune System. 1992. The macrophage. C. E. Lewis and J.O.D. McGee, eds., Oxford, U.K., IRL Press, pp 1-74.
8. Ayres LR, Récio Ados R, Burin SM, Pereira JC, Martins AC, Sampaio SV, de Castro FA, Pereira-Crott LS. (2015). Bothrops snake venoms and their isolated toxins, an L-amino acid oxidase and a serine protease, modulate human complement system pathways. J Venom Anim Toxins Incl Trop Dis., 21:29
9. Barros SF, Friedlanskaia I, Petricevich VL, Kipnis TL. (1998). Local inflammation, lethality and cytokine release in mice injected with B. atrox venom. Mediators of Inflammation, 7(5):339–346.
10. Barth MW, Hendrzak JA, Melnicoff MJ, Moraham PS. (1995). Review of the macrophage disappearance reaction. J Leukoc Biol, 57(3):361-367.
11. Bonavita AG, da Costa AS, Pires AL, Neves-Ferreira AG, Perales J, Cordeiro RS, Martins MA, e Silva PM. (2006). Contribution of mast cells and snake venom metalloproteinases to the hyperalgesia induced by Bothrops jararaca venom in rats. Toxicon, 47(8):885-893.
12. Carneiro, AS, Ribeiro OG, De Franco M, Cabrera W, Vorraro F, Ibañez, Starobinas N. (2008). Bothrops jararaca venom (BjV) induces differential leukocyte accumulation in mice genetically selected for acute inflammatory reaction: the role of host genetic background on expression of adhesion molecules and release of endogenous mediators. Toxicon, 52(5):619-627.
13. Carneiro, AS, Ribeiro OG, De Franco M, Cabrera W, Vorraro F, Siqueira M, Ibañez O, Starobinas N. (2002). Local inflammatory reaction induced by Bothrops jararaca venom differs in mice selected for acute inflammatory response. Toxicon, 40(11):1571-1579.
14. Cohn ZA, Benson B. (1965). The differentiation of mononuclear phagocytes: Morphology, cytochemistry, and biochemistry. Revista Médica, 121:153-170.
15. Condrea E. (1979). Exposure of human red blood cell membrane phospholipids to ringhals (Hemachatus haemachates) venom phospholipase A. A re-evaluation of substrate specificity reversal. Toxicon, 17(1):27-28.
16. Curi R, Newsholme P, Pithon-Curi TC, Pires-de-Melo M, García C, Homem-de-Bittencourt Jr. PI, Guimaraes ARP. (1999). Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils. Braz. J. Med. Biol, 32(1):15-21.
17. Edwards JP, Zhang X, Frauwirth KA, Mosser DM. (2006). Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol, 80:1298–1300.
18. Farsky S, Gonçalves L, Gutiérrez JM, Correa A, Rucavado A, Gasque P, Tambourgi D. (2000). Bothrops asper snake venom and its metalloproteinase BaP–1 activate the complement system. Role in leucocyte recruitment. Mediators of Inflammation, 9(5):213-222.
19. Ferraz CR, Calixto-Campos C, Manchope MF, Casagrande R, Clissa PB, Baldo C, Verri WA Jr. (2015). Jararhagin-induced mechanical hyperalgesia depends on TNF-α, IL-1β and NFκB in mice. Toxicon, 103:119-128.
20. Giannotti, KC, Leiguez E, Moreira V, Nascimento N, Lomonte B, Gutiérrez JM, Lopes de Melo R, Teixeira C. (2013). A Lys49 phospholipase A2, isolated from Bothrops asper snake venom, induces lipid droplet formation in macrophages which depends on distinct signaling pathways and the C-terminal region. Biomed Res Int, 807982.
21. Goñi M, Vaisberg A, Zavaleta A. (1992). Citotoxicidad inducida por veneno de serpientes peruanas sobre fibroblastos de ratón. Rev. Biol. Trop, 40(1):143-145.
22. Gutierrez JM, Cerdas L. Mecanismo de acción de miotoxinas aisladas de venenos de serpientes. Publicaciones de la Universidad de Costa Rica, Facultad de Microbiología, Instituto Clodomiro Picado, 1984.
23. Hernandez-Cruz A, Mendonça RZ, Petricevich VL. (2005). Crotalus durissus terrificus venom interferes with morphological, functional, and biochemical changes in murine macrophage. Mediators Inflamm, (6):349-359.
24. Holmes B, Quie PG, Windhorst DB, Good RA. (1996). Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function, Lancet, 1(7449):1225-1228.
25. Izidoro LF, Sobrinho J, Mendes M, Costa T, Grabner A, Rodrigues V, da Silva S, Zanchi F, Zuliani J, Fernandes C, Calderon L, Stábeli R, Soares A. (2014). Snake Venom L-Amino Acid Oxidases: Trends in Pharmacology and Biochemistry. BioMed Research International, 196754.
26. Leiguez E, Zuliani JP, Cianciarullo AM, Fernandes CM, Guttiérrez J M, Teixeira C. (2011). A group IIA-secreted phospholipase A2 from snake venom induces lipid body formation in macrophages: the roles of intracellular phospholipases A2 and distinct signaling pathways. J Leukoc Biol, 90(1):155-66.
27. Lomonte B, Gutierrez JM, Romero M, Nunez J, Tarkowski A, Hanson LA. (1993). An MTT-based method for the in vivo quantification of myotoxic activity of snake venoms and its neutralization by antibodies. Journal of Immunological Methods, 161(2):231–237.
28. Mandell GL. (1995). Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol, 25:S20–S22.
29. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol, 23(11):549-555.
30. Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010. 140(6):771-776.
31. Méndez A, Ruth M. Dosis letal 50 del veneno de Bothrops colombiensis y Bothrops Venezuelensis (serpentes, viperidae) en ratones NMRI y BALB/c. Tesis de Grado, 2009. Universidad de Oriente de Venezuela.
32. Mosser D, Edwards J. (2008). Exploring the full spectrum of macrophage activation. Nature reviews. Inmunology, 8(12):958-969.
33. Murphy Kenneth. Janeway´s Immunobiology. 8° Edición. ISBN10: 0815342438. 2011.
34. Pantigoso C, Escobar E, Yarlequé A. (2001). Aislamiento y caracterización de una miotoxina del veneno de la serpiente Bothrops brazili Hoge ,1953 (Ophidia: Viperidae). Rev Peru Biol, 8(2):136 - 148.
35. Petricevich VL. (2010). Scorpion Venom and the Inflammatory Response. Mediators Inflamm, 903295.
36. Petricevich VL, Barbosa L, Possani L.D. Therapeutic use of scorpion venom. Molecular Aspects of inflammation. 2014. ISBN: 978-81-308-0528-3.
37. Petricevich VL, Teixeira CFP, Tambourgi DV, Gutiérrez JM. (2000). Increments in serum cytokine and nitric oxide levels in mice injected with Bothrops asper and Bothrops jararaca snake venoms. Toxicon, 38(9):1253–1266.
38. Pick E, Mizel D. (1981). Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. Journal of Inmmunological Methods, 46: 2111–2126.
39. Pinho FM, Pereira ID. (2001). Ofidismo. Rev Ass Med Brasil, 47(1):24-29.
40. Rojas–Espinoza O, Arce-Paredes P. Fagocitosis: Mecanismos y consecuencias. Primera parte. Artículo de revisión. Inmunología. Consejo Nacional de Ciencia y Tecnología (CONACyT), 2003.
41. Rucavado A, Soto M, Kamiguti AS, Theakston RD, Fox JW, Escalante T, Gutierrez JM. (2001). Characterization of aspercetin, a platelet aggregating component from the venom of the snake Bothrops asper which induces thrombocytopenia and potentiates metalloproteinase-induced hemorrhage. Thromb. Haemost, 85 (4): 710-715.
42. Ruff MR, Gifford GE. (1980). Purification and physico-chemical characterization of rabbit tumor necrosis factor. Journal of Immunology, 25 (4): 1671-1677.
43. Sánchez-Ramón S, López-Longo FJ, Carreno L. (2011). Interleucinas en la fisiopatología de la artritis reumatoide: más allá de las citocinas proinflamatorias. Reumatol Clin, 6(S3):S20–S24.
44. Schumacher JH, O´Garra A, Schrader P, Van Kimmenade A, Bond MW, Mosmann TR, Coffman RL. (1998). Characterization of 4 monoclonal antibodies to mouse interleukin-5 and development of mouse and human IL-5 assay. Journal of Inmmunology, 141, 1576-81.
45. Sica A, Mantovani A. (2012). Macrophage plasticity and polarization: in vivo. J Clin Invest, 122(3):787-795.
46. Silva C, Zuliani J, Assakura M, Mentele R, Camargo A, Teixeira C, Serrano S. (2004). Activation of alpha(M)beta(2)-mediated phagocytosis by HF3, a P-III class metalloproteinase isolated from the venom of Bothrops jararaca. Biochem Biophys Res Commun, 322(3): 950-956.
47. Soto De Ferrini S, Maruñak S, Leiva L, Acosta De Pérez O, Rivero V. Efecto Citotóxico del veneno de B. jararacussu y su fosfolipasa A2 sobre células macrofágicas. 2008. Universidad Nacional del Nordeste Argentino.
48. Teixeira CFP, Zamuner SR, Zuliani JP, Fernandes CM, Cruz-Hofling MA, Fernandes I, Chaves F, Gutiérrez JM. (2003). Neutrophils do not contribute to local tissue damage, but play a key role in skeletal muscle regeneration, in mice injected with Bothrops asper snake venom. Muscle Nerve, 28, 449–459.
49. Thelestam M. (1979). Mechanism of action of cytolitic toxines human fibroblasts. Toxicon,17 (supl l): 127.
50. von Burg N, Turchinovich G, Finke D. (2015). Maintenance of Immune Homeostasis through ILC/T Cell Interactions. Front Immunol, 6:416.
51. Yamashiro E, Oliveira A, Kitano E, Menezes M, Junqueira de Azevedo I, Paes Leme A, Serrano S. (2014). Proteoforms of the platelet-aggregating enzyme PA-BJ, a serine proteinase from Bothrops jararaca venom. BBA Proteins and Proteomics, 1844 (12): 2068-2076.
52. Yamashita KM, Alves AF, Barbaro KC, Santoro ML. (2014). Bothrops jararaca venom metalloproteinases are essential for coagulopathy and increase plasma tissue factor levels during envenomation. PLosS Negl Trop Dis, 8(5):e2814.
53. Zamuner SR, Texeira CF. (2002). Cell adhesion molecules involved in the leukocyte recruitment induced by venom of the snake Bothrops jararaca. Mediators Inflamm, 11: 351-357.
54. Zebedee SL, Koduri RK, Mukherjee J, Lee S, Sauser DF, Scharff MD, Casadevall A. (1994). Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neuformans. Antimicrobial Agents Chemothe, (38): 150.
55. Zhang X, Mosser DM. (2008). Macrophage activation by endogenous danger signals. J. Pathol, 214: 161–178.
56. Zuliani, J, Gutierrez JM, Casais e Silva L, Sampaio S, Lomonte B, Pereira C. (2005). Activation of cellular functions in macrophages by venom secretory Asp-49 and Lys-49 phospholipases A(2). Toxicon, 46(5): 523-532.
1. Aderem A, Underhill DM. (1999). Mechanisms of phagocytosis in macrophages. Annu Rev Immunol, 17:593-623.
2. Aideen B, Denis R. (2001). Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils. The journal of immunology, 168(4):1968-1977.
3. Ande SR, Fussi H, Knauer H, Murkovic M, Ghisla S, Fröhlich KU, Macheroux P. (2008). Induction of apoptosis in yeast by L-amino acid oxidase from the Malayan pit viper Calloselasma rhodostoma. Yeast, 25(5):349–357.
4. Arandjelovic S, Bogic M, Raskovic S. (1998). The role of mononuclear phagocytes and dendritic cells in allergic inflammation. Srp Arh Celok Lek, 126(1-2):46-53.
5. Arruda, MS, Richi VB, Oliveira SM, Vilani-Moreno FR. (2004). Experimental murine mycobareriosis: Evaluation of the functional activity of alveolar macrophages in thalidomide- treated mice. Revista de Biología médica, 37:485-492.
6. Asega AF, Oliveira AK, Menezes MC, Neves-Ferreira AG, Serrano SM. (2014). Interaction of Bothrops jararaca venom metalloproteinases with protein inhibitors. Toxicon, 80:1-8.
7. Auger MJ, Ross JA. The biology of the macrophage. In The Natural Inmune System. 1992. The macrophage. C. E. Lewis and J.O.D. McGee, eds., Oxford, U.K., IRL Press, pp 1-74.
8. Ayres LR, Récio Ados R, Burin SM, Pereira JC, Martins AC, Sampaio SV, de Castro FA, Pereira-Crott LS. (2015). Bothrops snake venoms and their isolated toxins, an L-amino acid oxidase and a serine protease, modulate human complement system pathways. J Venom Anim Toxins Incl Trop Dis., 21:29
9. Barros SF, Friedlanskaia I, Petricevich VL, Kipnis TL. (1998). Local inflammation, lethality and cytokine release in mice injected with B. atrox venom. Mediators of Inflammation, 7(5):339–346.
10. Barth MW, Hendrzak JA, Melnicoff MJ, Moraham PS. (1995). Review of the macrophage disappearance reaction. J Leukoc Biol, 57(3):361-367.
11. Bonavita AG, da Costa AS, Pires AL, Neves-Ferreira AG, Perales J, Cordeiro RS, Martins MA, e Silva PM. (2006). Contribution of mast cells and snake venom metalloproteinases to the hyperalgesia induced by Bothrops jararaca venom in rats. Toxicon, 47(8):885-893.
12. Carneiro, AS, Ribeiro OG, De Franco M, Cabrera W, Vorraro F, Ibañez, Starobinas N. (2008). Bothrops jararaca venom (BjV) induces differential leukocyte accumulation in mice genetically selected for acute inflammatory reaction: the role of host genetic background on expression of adhesion molecules and release of endogenous mediators. Toxicon, 52(5):619-627.
13. Carneiro, AS, Ribeiro OG, De Franco M, Cabrera W, Vorraro F, Siqueira M, Ibañez O, Starobinas N. (2002). Local inflammatory reaction induced by Bothrops jararaca venom differs in mice selected for acute inflammatory response. Toxicon, 40(11):1571-1579.
14. Cohn ZA, Benson B. (1965). The differentiation of mononuclear phagocytes: Morphology, cytochemistry, and biochemistry. Revista Médica, 121:153-170.
15. Condrea E. (1979). Exposure of human red blood cell membrane phospholipids to ringhals (Hemachatus haemachates) venom phospholipase A. A re-evaluation of substrate specificity reversal. Toxicon, 17(1):27-28.
16. Curi R, Newsholme P, Pithon-Curi TC, Pires-de-Melo M, García C, Homem-de-Bittencourt Jr. PI, Guimaraes ARP. (1999). Metabolic fate of glutamine in lymphocytes, macrophages and neutrophils. Braz. J. Med. Biol, 32(1):15-21.
17. Edwards JP, Zhang X, Frauwirth KA, Mosser DM. (2006). Biochemical and functional characterization of three activated macrophage populations. J. Leukoc. Biol, 80:1298–1300.
18. Farsky S, Gonçalves L, Gutiérrez JM, Correa A, Rucavado A, Gasque P, Tambourgi D. (2000). Bothrops asper snake venom and its metalloproteinase BaP–1 activate the complement system. Role in leucocyte recruitment. Mediators of Inflammation, 9(5):213-222.
19. Ferraz CR, Calixto-Campos C, Manchope MF, Casagrande R, Clissa PB, Baldo C, Verri WA Jr. (2015). Jararhagin-induced mechanical hyperalgesia depends on TNF-α, IL-1β and NFκB in mice. Toxicon, 103:119-128.
20. Giannotti, KC, Leiguez E, Moreira V, Nascimento N, Lomonte B, Gutiérrez JM, Lopes de Melo R, Teixeira C. (2013). A Lys49 phospholipase A2, isolated from Bothrops asper snake venom, induces lipid droplet formation in macrophages which depends on distinct signaling pathways and the C-terminal region. Biomed Res Int, 807982.
21. Goñi M, Vaisberg A, Zavaleta A. (1992). Citotoxicidad inducida por veneno de serpientes peruanas sobre fibroblastos de ratón. Rev. Biol. Trop, 40(1):143-145.
22. Gutierrez JM, Cerdas L. Mecanismo de acción de miotoxinas aisladas de venenos de serpientes. Publicaciones de la Universidad de Costa Rica, Facultad de Microbiología, Instituto Clodomiro Picado, 1984.
23. Hernandez-Cruz A, Mendonça RZ, Petricevich VL. (2005). Crotalus durissus terrificus venom interferes with morphological, functional, and biochemical changes in murine macrophage. Mediators Inflamm, (6):349-359.
24. Holmes B, Quie PG, Windhorst DB, Good RA. (1996). Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function, Lancet, 1(7449):1225-1228.
25. Izidoro LF, Sobrinho J, Mendes M, Costa T, Grabner A, Rodrigues V, da Silva S, Zanchi F, Zuliani J, Fernandes C, Calderon L, Stábeli R, Soares A. (2014). Snake Venom L-Amino Acid Oxidases: Trends in Pharmacology and Biochemistry. BioMed Research International, 196754.
26. Leiguez E, Zuliani JP, Cianciarullo AM, Fernandes CM, Guttiérrez J M, Teixeira C. (2011). A group IIA-secreted phospholipase A2 from snake venom induces lipid body formation in macrophages: the roles of intracellular phospholipases A2 and distinct signaling pathways. J Leukoc Biol, 90(1):155-66.
27. Lomonte B, Gutierrez JM, Romero M, Nunez J, Tarkowski A, Hanson LA. (1993). An MTT-based method for the in vivo quantification of myotoxic activity of snake venoms and its neutralization by antibodies. Journal of Immunological Methods, 161(2):231–237.
28. Mandell GL. (1995). Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol, 25:S20–S22.
29. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol, 23(11):549-555.
30. Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010. 140(6):771-776.
31. Méndez A, Ruth M. Dosis letal 50 del veneno de Bothrops colombiensis y Bothrops Venezuelensis (serpentes, viperidae) en ratones NMRI y BALB/c. Tesis de Grado, 2009. Universidad de Oriente de Venezuela.
32. Mosser D, Edwards J. (2008). Exploring the full spectrum of macrophage activation. Nature reviews. Inmunology, 8(12):958-969.
33. Murphy Kenneth. Janeway´s Immunobiology. 8° Edición. ISBN10: 0815342438. 2011.
34. Pantigoso C, Escobar E, Yarlequé A. (2001). Aislamiento y caracterización de una miotoxina del veneno de la serpiente Bothrops brazili Hoge ,1953 (Ophidia: Viperidae). Rev Peru Biol, 8(2):136 - 148.
35. Petricevich VL. (2010). Scorpion Venom and the Inflammatory Response. Mediators Inflamm, 903295.
36. Petricevich VL, Barbosa L, Possani L.D. Therapeutic use of scorpion venom. Molecular Aspects of inflammation. 2014. ISBN: 978-81-308-0528-3.
37. Petricevich VL, Teixeira CFP, Tambourgi DV, Gutiérrez JM. (2000). Increments in serum cytokine and nitric oxide levels in mice injected with Bothrops asper and Bothrops jararaca snake venoms. Toxicon, 38(9):1253–1266.
38. Pick E, Mizel D. (1981). Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. Journal of Inmmunological Methods, 46: 2111–2126.
39. Pinho FM, Pereira ID. (2001). Ofidismo. Rev Ass Med Brasil, 47(1):24-29.
40. Rojas–Espinoza O, Arce-Paredes P. Fagocitosis: Mecanismos y consecuencias. Primera parte. Artículo de revisión. Inmunología. Consejo Nacional de Ciencia y Tecnología (CONACyT), 2003.
41. Rucavado A, Soto M, Kamiguti AS, Theakston RD, Fox JW, Escalante T, Gutierrez JM. (2001). Characterization of aspercetin, a platelet aggregating component from the venom of the snake Bothrops asper which induces thrombocytopenia and potentiates metalloproteinase-induced hemorrhage. Thromb. Haemost, 85 (4): 710-715.
42. Ruff MR, Gifford GE. (1980). Purification and physico-chemical characterization of rabbit tumor necrosis factor. Journal of Immunology, 25 (4): 1671-1677.
43. Sánchez-Ramón S, López-Longo FJ, Carreno L. (2011). Interleucinas en la fisiopatología de la artritis reumatoide: más allá de las citocinas proinflamatorias. Reumatol Clin, 6(S3):S20–S24.
44. Schumacher JH, O´Garra A, Schrader P, Van Kimmenade A, Bond MW, Mosmann TR, Coffman RL. (1998). Characterization of 4 monoclonal antibodies to mouse interleukin-5 and development of mouse and human IL-5 assay. Journal of Inmmunology, 141, 1576-81.
45. Sica A, Mantovani A. (2012). Macrophage plasticity and polarization: in vivo. J Clin Invest, 122(3):787-795.
46. Silva C, Zuliani J, Assakura M, Mentele R, Camargo A, Teixeira C, Serrano S. (2004). Activation of alpha(M)beta(2)-mediated phagocytosis by HF3, a P-III class metalloproteinase isolated from the venom of Bothrops jararaca. Biochem Biophys Res Commun, 322(3): 950-956.
47. Soto De Ferrini S, Maruñak S, Leiva L, Acosta De Pérez O, Rivero V. Efecto Citotóxico del veneno de B. jararacussu y su fosfolipasa A2 sobre células macrofágicas. 2008. Universidad Nacional del Nordeste Argentino.
48. Teixeira CFP, Zamuner SR, Zuliani JP, Fernandes CM, Cruz-Hofling MA, Fernandes I, Chaves F, Gutiérrez JM. (2003). Neutrophils do not contribute to local tissue damage, but play a key role in skeletal muscle regeneration, in mice injected with Bothrops asper snake venom. Muscle Nerve, 28, 449–459.
49. Thelestam M. (1979). Mechanism of action of cytolitic toxines human fibroblasts. Toxicon,17 (supl l): 127.
50. von Burg N, Turchinovich G, Finke D. (2015). Maintenance of Immune Homeostasis through ILC/T Cell Interactions. Front Immunol, 6:416.
51. Yamashiro E, Oliveira A, Kitano E, Menezes M, Junqueira de Azevedo I, Paes Leme A, Serrano S. (2014). Proteoforms of the platelet-aggregating enzyme PA-BJ, a serine proteinase from Bothrops jararaca venom. BBA Proteins and Proteomics, 1844 (12): 2068-2076.
52. Yamashita KM, Alves AF, Barbaro KC, Santoro ML. (2014). Bothrops jararaca venom metalloproteinases are essential for coagulopathy and increase plasma tissue factor levels during envenomation. PLosS Negl Trop Dis, 8(5):e2814.
53. Zamuner SR, Texeira CF. (2002). Cell adhesion molecules involved in the leukocyte recruitment induced by venom of the snake Bothrops jararaca. Mediators Inflamm, 11: 351-357.
54. Zebedee SL, Koduri RK, Mukherjee J, Lee S, Sauser DF, Scharff MD, Casadevall A. (1994). Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neuformans. Antimicrobial Agents Chemothe, (38): 150.
55. Zhang X, Mosser DM. (2008). Macrophage activation by endogenous danger signals. J. Pathol, 214: 161–178.
56. Zuliani, J, Gutierrez JM, Casais e Silva L, Sampaio S, Lomonte B, Pereira C. (2005). Activation of cellular functions in macrophages by venom secretory Asp-49 and Lys-49 phospholipases A(2). Toxicon, 46(5): 523-532.