Modulação imune de macrófagos: influência do TGF-β1 na dinâmica da IL-1β na infecção pelo vírus da dengue
DOI:
https://doi.org/10.5281/zenodo.13741644Palavras-chave:
dengue, macrófago, IL-1ß, TGF-ß1, inflamação, imunidade inataResumo
Introdução: vários mecanismos patogênicos contribuem para a gravidade da infecção pelo vírus da dengue. Isso inclui citotoxicidade viral, genética do hospedeiro e comorbidades como diabetes e dislipidemia. Pacientes com dengue grave apresentam resposta imune descontrolada com altos níveis de citocinas pró-inflamatórias (TNF, IL-1β, IL-8, IL-6) e quimiocinas, que danificam o endotélio microvascular. As citocinas antiinflamatórias (IL-4, IL-10 e TGF-β1) também estão aumentadas. O papel do TGF-β1 na dengue permanece obscuro. Existem poucos estudos e a maioria deles utiliza dados séricos de pacientes. Estes sugerem efeitos protetores e prejudiciais.
Objetivo: este estudo teve como objetivo avaliar como o TGF-β1 regula a secreção de IL-1β em macrófagos infectados com dengue in vitro, isto foi realizado no laboratório de imunidade inata, na Universidade Autônoma del Estado de Morelos, México.
Método: a linhagem celular THP-1 foi tratada com TGF-β1 recombinante antes ou após a infecção pelo vírus da dengue (DENV). As células foram diferenciadas em macrófagos por PMA. Os dados foram obtidos por meio de ensaios RT-PCR, IFA e ELISA. As variáveis analisadas incluíram a expressão e secreção de IL-1β. A análise estatística incluiu testes t de Student.
Resultados: a RT-PCR mostrou que a expressão de IL-1β foi semelhante nas células pré-tratadas e controle. No entanto, a secreção de IL-1β diminuiu apenas quando as células foram estimuladas com TGF-β1 antes da infecção. O tratamento após a infecção não teve efeito. O bloqueio do receptor TGF-β1 (SB505124) antes do tratamento com TGF-β1 e da infecção por DENV anulou o efeito inibitório do TGF-β1.
Conclusões: esses achados sugerem que o DENV poderia regular a função do TGF-β1 em macrófagos. A regulação negativa da via do TGF-β1 é potencialmente um mecanismo pelo qual o DENV evita a resposta imune. Isso poderia contribuir para a imunopatologia.
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Referências
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22. Pang T, Cardosa MJ, Guzman MG. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol [Internet]. 2007 Jan [cited 14 May 2024]; 85(1):43–5. DOI: https://doi.org/10.1038/sj.icb.7100008
23. Yacoub S, Wills B. Predicting outcome from dengue. BMC Med [Internet]. 2014 Dec [cited 14 May 2024]; 12(1):1–10. DOI: https://doi.org/10.1186/s12916-014-0147-9
24. John DV, Lin YS, Perng GC. Biomarkers of severe dengue disease – a review. J Biomed Sci [Internet]. 2015 Oct [cited 14 May 2024]; 22:83. DOI: https://doi.org/10.1186/s12929-015-0191-6
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2. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet [Internet]. 2018 Nov [cited 14 May 2024]; 392(10159):1736–88. DOI: https://doi.org/10.1016/s0140-6736(18)32203-7
3. Martinez JD, Garza JAC de la, Cuellar-Barboza A. Going Viral 2019: Zika, Chikungunya, and Dengue. Dermatol Clin [Internet]. 2019 Jan [cited 14 May 2024]; 37(1):95–105. DOI: https://doi.org/10.1016/j.det.2018.07.008
4. Wilder-Smith A, Ooi EE, Horstick O, Wills B. Dengue. Lancet Lond Engl [Internet]. 2019 Jan 26 [cited 14 May 2024]; 393(10169):350–63. DOI: https://doi.org/10.1016/s0140-6736(18)32560-1
5. Pandey N, Jain A, Garg RK, Kumar R, Agrawal OP, Lakshmana Rao PV. Serum levels of IL-8, IFNγ, IL-10, and TGF β and their gene expression levels in severe and non-severe cases of dengue virus infection. Arch Virol [Internet]. 2015 Jun [cited 14 May 2024]; 160(6):1463–75. DOI: https://doi.org/10.1007/s00705-015-2410-6
6. Patra G, Mallik S, Saha B, Mukhopadhyay S. Assessment of chemokine and cytokine signatures in patients with dengue infection: A hospital-based study in Kolkata, India. Acta Trop [Internet]. 2019 Feb [cited 14 May 2024]; 190:73–9. DOI: https://doi.org/10.1016/j.actatropica.2018.10.017
7. Soo KM, Khalid B, Ching SM, Tham CL, Basir R, Chee HY. Meta-analysis of biomarkers for severe dengue infections. PeerJ [Internet]. 2017 Sep [cited 14 May 2024]; 5:e3589. DOI: https://doi.org/10.7717/peerj.3589
8. Srikiatkhachorn A, Mathew A, Rothman AL. Immune-mediated cytokine storm and its role in severe dengue. Semin Immunopathol [Internet]. 2017 Jul [cited 14 May 2024]; 39(5):563–74. DOI: https://doi.org/10.1007/s00281-017-0625-1
9. Palmal S, Kundu S, Ganguly S, Dey JB, Sandhukhan S, Pattanayak AK. Immunologic Crosstalk and Host-Specific Immune Signature Associated with Dengue. ACS Omega [Internet]. 2024 Aug [cited 30 Dic 2024]; 9(36):37418–29. DOI: https://doi.org/10.1021/acsomega.4c02506
10. St. John AL, Rathore APS. Adaptive immune responses to primary and secondary dengue virus infections. Nat Rev Immunol [Internet]. 2019 Apr [cited 14 May 2024]; 19(4):218–30. DOI: https://doi.org/10.1038/s41577-019-0123-x
11. Bozza FA, Cruz OG, Zagne SM, Azeredo EL, Nogueira RM, Assis EF, Bozza PT, Kubelka CF. Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis [Internet]. 2008 Jun [cited 14 May 2024]; 8:86. DOI: https://doi.org/10.1186/1471-2334-8-86
12. Chaturvedi UC, Nagar R, Shrivastava R. Macrophage and dengue virus: friend or foe? Indian J Med Res [Internet]. 2006 Jul [cited 14 May 2024]; 124(1):23–40. Disponible en: https://pubmed.ncbi.nlm.nih.gov/16926454/
13. Huyen TB, Trieu HT, Vuong NL, Minh Nguyet N, Tam DTH, McBride A, et al. Anakinra for dengue patients with hyperinflammation: protocol for a randomized double-blind placebo-controlled trial. Wellcome Open Res [Internet]. 2024 [cited 30 Dic 2024]; 9:689. DOI: https://doi.org/10.12688/wellcomeopenres.21017.1
14. Agarwal R, Elbishbishi EA, Chaturvedi UC, Nagar R, Mustafa AS. Profile of transforming growth factor-beta 1 in patients with dengue haemorrhagic fever. Int J Exp Pathol [Internet]. 1999 Jun [cited 14 May 2024]; 80(3):143–9. DOI: https://doi.org/10.1046/j.1365-2613.1999.00107.x
15. Laur F, Murgue B, Deparis X, Roche C, Cassar O, Chungue E. Plasma levels of tumour necrosis factor a and transforming growth factor β-1 in children with dengue 2 virus infection in French Polynesia. Trans R Soc Trop Med Hyg [Internet]. 1998 [cited 14 May 2024]; 92(6):654–6. DOI: https://doi.org/10.1016/s0035-9203(98)90800-8
16. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-β1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol [Internet]. 2010 Nov [cited 14 May 2024]; 71(11):1135–40. DOI: https://doi.org/10.1016/j.humimm.2010.08.004
17. Yeo ASL, Azhar NA, Yeow W, Talbot CC, Khan MA, Shankar EM, et al. Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes. PloS One [Internet]. 2014 [cited 14 May 2024]; 9(4):e92240. DOI: https://doi.org/10.1371/journal.pone.0092240
18. Tillu H, Tripathy AS, Reshmi PV, Cecilia D. Altered profile of regulatory T cells and associated cytokines in mild and moderate dengue. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol [Internet]. 2016 Mar [cited 14 May 2024]; 35(3):453–61. DOI: https://doi.org/10.1007/s10096-015-2561-0
19. Lee YS, Kim JH, Kim ST, Kwon JY, Hong S, Kim SJ, et al. Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-beta1-induced negative regulation of IL-1R/TLR signaling. Biochem Biophys Res Commun [Internet]. 2010 Mar 19 [cited 14 May 2024]; 393(4):836–43. DOI: https://doi.org/10.1016/j.bbrc.2010.02.094
20. Imai K, Takeshita A, Hanazawa S. Transforming Growth Factor-β Inhibits Lipopolysaccharide-Stimulated Expression of Inflammatory Cytokines in Mouse Macrophages through Downregulation of Activation Protein 1 and CD14 Receptor Expression. Infect Immun [Internet]. 2000 May [cited 14 May 2024]; 68(5):2418–23. DOI: https://doi.org/10.1128/iai.68.5.2418-2423.2000
21. Tsatsanis C, Androulidaki A, Dermitzaki E, Gravanis A, Margioris AN. Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2. J Cell Physiol [Internet]. 2007 [cited 14 May 2024]; 210(3):774–83. DOI: https://doi.org/10.1002/jcp.20900
22. Pang T, Cardosa MJ, Guzman MG. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol [Internet]. 2007 Jan [cited 14 May 2024]; 85(1):43–5. DOI: https://doi.org/10.1038/sj.icb.7100008
23. Yacoub S, Wills B. Predicting outcome from dengue. BMC Med [Internet]. 2014 Dec [cited 14 May 2024]; 12(1):1–10. DOI: https://doi.org/10.1186/s12916-014-0147-9
24. John DV, Lin YS, Perng GC. Biomarkers of severe dengue disease – a review. J Biomed Sci [Internet]. 2015 Oct [cited 14 May 2024]; 22:83. DOI: https://doi.org/10.1186/s12929-015-0191-6
25. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol [Internet]. 1998 [cited 14 May 2024]; 16:137–61. DOI: https://doi.org/10.1146/annurev.immunol.16.1.137
26. Djamiatun K, Faradz SMH, Setiati TE, Netea MG, van der Ven AJAM, Dolmans WMV. Increase of plasminogen activator inhibitor-1 and decrease of transforming growth factor-b1 in children with dengue haemorrhagic fever in Indonesia. J Trop Pediatr [Internet]. 2011 Dec [cited 14 May 2024]; 57(6):424–32. DOI: https://doi.org/10.1093/tropej/fmq122
27. Sierra B, Perez AB, Vogt K, Garcia G, Schmolke K, Aguirre E, et al. Secondary heterologous dengue infection risk: Disequilibrium between immune regulation and inflammation? Cell Immunol [Internet]. 2010 [cited 14 May 2024]; 262(2):134–40. DOI: https://doi.org/10.1016/j.cellimm.2010.02.005
28. Chen W, Ten Dijke P. Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol [Internet]. 2016 Nov [cited 14 May 2024]; 16(12):723–40. DOI: https://doi.org/10.1038/nri.2016.112
29. Li MO, Flavell RA. TGF-beta, T-cell tolerance and immunotherapy of autoimmune diseases and cancer. Expert Rev Clin Immunol [Internet]. 2006 Mar [cited 14 May 2024]; 2(2):257–65. DOI: https://doi.org/10.1586/1744666x.2.2.257
30. Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol [Internet]. 2014 [cited 14 May 2024]; 32:51–82. DOI: https://doi.org/10.1146/annurev-immunol-032713-120257
31. Callaway JB, Smith SA, McKinnon KP, de Silva AM, Crowe JE, Ting JPY. Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection. J Biol Chem [Internet]. 2015 Jul 10 [cited 14 May 2024]; 290(28):17306–20. DOI: https://doi.org/10.1074/jbc.m115.664136
32. Kwon YJ, Heo J, Wong HEE, Cruz DJM, Velumani S, da Silva CT, et al. Kinome siRNA screen identifies novel cell-type specific dengue host target genes. Antiviral Res [Internet]. 2014 Oct [cited 14 May 2024]; 110:20–30. DOI: https://doi.org/10.1016/j.antiviral.2014.07.006
33. Brough D, Pelegrin P, Nickel W. An emerging case for membrane pore formation as a common mechanism for the unconventional secretion of FGF2 and IL-1β. J Cell Sci [Internet]. 2017 Oct [cited 14 May 2024]; 130(19):3197–202. DOI: https://doi.org/10.1242/jcs.204206
34. New J, Thomas SM. Autophagy-dependent secretion: mechanism, factors secreted, and disease implications. Autophagy [Internet]. 2019 Oct [cited 14 May 2024]; 15(10):1682–93. DOI: https://doi.org/10.1080/15548627.2019.1596479
35. Wu MF, Chen ST, Yang AH, Lin WW, Lin YL, Chen NJ, et al. CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages. Blood [Internet]. 2013 Jan 3 [cited 14 May 2024]; 121(1):95–106. DOI: https://doi.org/10.1182/blood-2012-05-430090
36. Tan TY, Chu JJH. Dengue virus-infected human monocytes trigger late activation of caspase-1, which mediates pro-inflammatory IL-1β secretion and pyroptosis. J Gen Virol [Internet]. 2013 Oct [cited 14 May 2024]; 94(Pt 10):2215–20. DOI: https://doi.org/10.1099/vir.0.055277-0
37. Cheung KT, Sze DMY, Chan KH, Leung PHM. Involvement of caspase-4 in IL-1 beta production and pyroptosis in human macrophages during dengue virus infection. Immunobiology [Internet]. 2018 [cited 14 May 2024]; 223(4–5):356–64. DOI: https://doi.org/10.1016/j.imbio.2017.10.044
38. Netea MG, Veerdonk FL van de, Meer JWM van der, Dinarello CA, Joosten LAB. Inflammasome-Independent Regulation of IL-1-Family Cytokines. Annu Rev Immunol [Internet]. 2015 Mar [cited 14 May 2024]; 33:49–77.DOI: https://doi.org/10.1146/annurev-immunol-032414-112306
39. Harris J. Autophagy and cytokines. Cytokine [Internet]. 2011 Nov [cited 14 May 2024]; 56(2):140–4. DOI: https://doi.org/10.1016/j.cyto.2011.08.022
40. Harris J. Autophagy and IL-1 Family Cytokines. Front Immunol [Internet]. 2013 Apr 5 [cited 14 May 2024]; 4:83. DOI: https://doi.org/10.3389/fimmu.2013.00083
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2025-03-20
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Serrato Salas J, Ramírez Agüero B, Montiel Hernández JL, González Christen J. Modulação imune de macrófagos: influência do TGF-β1 na dinâmica da IL-1β na infecção pelo vírus da dengue. Rev Inf Cient [Internet]. 20º de março de 2025 [citado 4º de abril de 2025];104:e4791. Disponível em: https://revinfcientifica.sld.cu/index.php/ric/article/view/4791
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Copyright (c) 2025 Javier Serrato Salas, Brenda Ramírez Agüero, José Luis Montiel Hernández, Judith González Christen
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
