Skip to main content

Advertisement

SpringerLink
Log in

Novel role of toll-like receptor 3, RIG-I and MDA5 in poly (I:C) RNA-induced mesothelial inflammation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Viral inflammation and infection of mesothelial cells (MC) are a major problem in several organ systems including pleura, pericardium and peritoneum. Toll-like receptors (TLRs) are an essential part of the innate immune system for early recognition of pathogen-associated molecular patterns. TLRs recognise molecular patterns associated with microbial pathogens and induce an immune response. TLR3 recognises dsRNA of viral origin as exemplified by poly (I:C) RNA, a synthetic analogue of viral dsRNA. The helicases RIG-I and MDA5 may also act as sensors of viral infections. MC exhibit an expression of TLR3, RIG-I and MDA5. Poly (I:C) RNA stimulation resulted in an up-regulation of proinflammatory cytokines and chemokines as well as type I interferons. This novel finding of functional expression of viral sensors on human MC may indicate a novel link between viral infections and mesothelial inflammation and indicates a pathophysiologic role of viral receptors in these processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Bryant-Greenwood P, Sorbara L, Lilie AC, Little R, Yarchoan R, Wilson W, Raffeld M, Abati A (2003) Infection of mesothelial cells with human herpes virus 8 in human immunodeficiency virus-infected patients with Kaposi’s sarcoma, Castleman’s disease, and recurrent pleural effusions. Mod Pathol 16:1299–1300. doi:10.1097/01.MP.0000052374.61768.79

    Article  Google Scholar 

  2. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332:1186–1191. doi:10.1056/NEJM199505043321802

    Article  PubMed  CAS  Google Scholar 

  3. Gessain A, Briere J, Angelin-Duclos C, Valensi F, Beral HM, Davi F, Nicola MA, Sudaka A, Fouchard N, Gabarre J, Troussard X, Dulmet E, Audouin J, Diebold J, de The G (1997) Human herpes virus 8 (Kaposi’s sarcoma herpes virus) and malignant lymphoproliferations in France: a molecular study of 250 cases including two AIDS-associated body cavity based lymphomas. Leukemia 11:266–272. doi:10.1038/sj.leu.2400549

    Article  PubMed  CAS  Google Scholar 

  4. Ramos-Nino ME, Testa JR, Altomare DA, Pass HI, Carbone M, Bocchetta M, Mossman BT (2006) Cellular and molecular parameters of mesothelioma. J Cell Biochem 98:723–734. doi:10.1002/jcb.20828

    Article  PubMed  CAS  Google Scholar 

  5. Jaurand MC, Fleury-Feith J (2005) Pathogenesis of malignant pleural mesothelioma. Respirology 10:2–8. doi:10.1111/j.1440-1843.2005.00694.x

    Article  PubMed  Google Scholar 

  6. Carbone M, Burck C, Rdzanek M, Rudzinski J, Cutrone R, Bocchetta M (2003) Different susceptibility of human mesothelial cells to polyomavirus infection and malignant transformation. Cancer Res 63:6125–6129

    PubMed  CAS  Google Scholar 

  7. Kandolf R, Klingel K, Zell R, Canu A, Fortmuller U, Hohenadl C, Albrecht M, Reimann BY, Franz WM, Heim A (1993) Molecular mechanisms in the pathogenesis of enteroviral heart disease: acute and persistent infections. Clin Immunol Immunopathol 68:153–158. doi:10.1006/clin.1993.1112

    Article  PubMed  CAS  Google Scholar 

  8. Katsivas T, Sokolov R, Miller M, Hever A, Hu B (2004) Primary herpetic peritonitis causing intestinal perforation: case report and review of the literature. Clin Infect Dis 39:13–16. doi:10.1086/421998

    Article  Google Scholar 

  9. Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680. doi:10.1038/90609

    Article  PubMed  CAS  Google Scholar 

  10. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216. doi:10.1146/annurev.immunol.20.083001.084359

    Article  PubMed  CAS  Google Scholar 

  11. Medzhitov R, Janeway CA Jr (1997) Innate immunity: the virtues of non-clonal system of recognition. Cell 91:295–298. doi:10.1016/S0092-8674(00)80412-2

    Article  PubMed  CAS  Google Scholar 

  12. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–1526. doi:10.1126/science.1094351

    Article  PubMed  CAS  Google Scholar 

  13. Anders HJ, Banas B, Schlöndorff D (2004) Signaling danger: toll-like receptors and their potential roles in kidney disease. J Am Soc Nephrol 15:854–867. doi:10.1097/01.ASN.0000121781.89599.16

    Article  PubMed  CAS  Google Scholar 

  14. Matsumoto M, Kikkawa S, Kohase M, Miyake K, Seya T (2002) Establishment of a monoclonal antibody against human toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem Biophys Res Commun 293:1364–1369. doi:10.1016/S0006-291X(02)00380-7

    Article  PubMed  CAS  Google Scholar 

  15. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-κB by toll-like receptor 3. Nature 413:732–738. doi:10.1038/35099560

    Article  PubMed  CAS  Google Scholar 

  16. Wörnle M, Schmid H, Banas B, Merkle M, Henger A, Roeder M, Blattner S, Bock E, Kretzler M, Gröne HJ, Schlöndorff D (2006) Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol 168:370–385. doi:10.2353/ajpath.2006.050491

    Article  PubMed  Google Scholar 

  17. Zarember KA, Godowski PJ (2002) Tissue expression of human toll-like receptors and differential regulation of toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561

    PubMed  CAS  Google Scholar 

  18. Le Goffic R, Pothlichet J, Vitour D, Fujita T, Meurs E, Chignard M, Si-Tahar M (2007) Cutting edge: influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol 178:3368–3372

    PubMed  CAS  Google Scholar 

  19. Cario E, Podolsky DK (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010–7017. doi:10.1128/IAI.68.12.7010-7017.2000

    Article  PubMed  CAS  Google Scholar 

  20. Akira S (2001) Toll-like receptors and innate immunity. Adv Immunol 78:1–56. doi:10.1016/S0065-2776(01)78001-7

    Article  PubMed  CAS  Google Scholar 

  21. Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto Y, Yamamoto A, Seya T (2003) Subcellular localization of toll-like receptor 3 in human dendritic cells. J Immunol 171:3154–3162

    PubMed  CAS  Google Scholar 

  22. Kato S, Yuzawa Y, Tsuboi N, Maruyama S, Morita Y, Matsuguchi T, Matsuo S (2004) Endotoxin-induced chemokine expression in murine peritoneal mesothelial cells: the role of toll-like receptor 4. J Am Soc Nephrol 15:1289–1299

    PubMed  CAS  Google Scholar 

  23. Yount JS, Moran TM, Lopet CB (2007) Cytokine-independent upregulation of MDA5 in viral infection. J Virol 81:7316–7319. doi:10.1128/JVI.00545-07

    Article  PubMed  CAS  Google Scholar 

  24. Vitour D, Meurs EF (2007) Regulation of interferon production by RIG-I and LGP2: a lesson in self-control. Sci STKE 384:20

    Google Scholar 

  25. Yakulis R, Babinchak TJ (1999) Herpes simplex peritonitis: case report. Clin Infect Dis 28:1212–1215. doi:10.1086/514798

    Article  PubMed  CAS  Google Scholar 

  26. Struijk DG, van Ketel RJ, Krediet RT, Boeschoten EW, Arisz L (1986) Viral peritonitis in a continuous ambulatory peritoneal dialysis patient. Nephron 44:384. doi:10.1159/000124673

    Article  PubMed  CAS  Google Scholar 

  27. Lewis SL (1991) Recurrent peritonitis: evidence for possible viral etiology. Am J Kidney Dis 17:343–345

    PubMed  CAS  Google Scholar 

  28. Shulman LM, Rudich C, Sayar Y, Goldfeld G, Mendelson E, Blau A, Vonsover A (1992) Detection of CMV-DNA in cells from peritoneal fluid of IPD/CAPD patients by polymerase chain reaction. Adv Perit Dial 8:258–264

    PubMed  CAS  Google Scholar 

  29. Tekstra J, Visser CE, Tuk CW, Brouwer-Steenbergen JJ, Burger CW, Krediet RT, Beelen RH (1996) Identification of the major chemokines that regulate cell influxes in peritoneal dialysis patients. J Am Soc Nephrol 7:2379–2384

    PubMed  CAS  Google Scholar 

  30. Ajuebor MN, Flower RJ, Hannon R, Christie M, Bowers K, Verity A, Perretti M (1998) Endogenous monocyte chemoattractant protein-1 recruits monocytes in the zymosan peritonitis model. J Leukoc Biol 63:108–116

    PubMed  CAS  Google Scholar 

  31. Haslinger B, Mandl-Weber S, Sellmayer A, Lederer S, Sitter T (2001) Effect of high glucose concentration on the synthesis of monocyte chemoattractant protein-1 in human peritoneal mesothelial cells: involvement of protein kinase C. Nephron 87:346–351. doi:10.1159/000045941

    Article  PubMed  CAS  Google Scholar 

  32. Li FK, Davenport A, Robson RL, Loetscher P, Rothlein R, Williams JD, Topley N (1998) Leukocyte migration across human peritoneal mesothelial cells is dependent on directed chemokine secretion and ICAM-1 expression. Kidney Int 54:2170–2183. doi:10.1046/j.1523-1755.1998.00174.x

    Article  PubMed  CAS  Google Scholar 

  33. Topley N, Brown Z, Jorres A, Westwick J, Davies M, Coles GA, Williams JD (1993) Human peritoneal mesothelial cells synthesize IL-8: synergistic induction by interleukin-1 beta and tumor necrosis factor-alpha. Am J Pathol 142:1876–1886

    PubMed  CAS  Google Scholar 

  34. Betjes MGH, Tuk CW, Struijk DG, Kresiet RT, Arisz L, Hart M, Beelen RH (1993) Interleukin-8 production by human peritoneal mesothelial cells in response to tumor necrosis factor-alpha, interleukin-1, and medium conditioned by macrophages co-cultured with Staphylococcus epidermidis. J Infect Dis 168:1202–1210

    PubMed  CAS  Google Scholar 

  35. Topley N, Mackenzie RK, Williams JD (1996) Macrophages and mesothelial cells in bacterial peritonitis. Immunobiology 195:563–573

    PubMed  CAS  Google Scholar 

  36. van Hinsbergh VW, Kooistra T, Scheffer MA, Hajo van Bockel J, van Muijen GN (1990) Characterization and fibrinolytic properties of human omental tissue mesothelial cells. Comparison with endothelial cells. Blood 75:1490–1497

    PubMed  Google Scholar 

  37. Mack M, Kleinschmidt A, Brühl H, Klier C, Nelson PJ, Cihak J, Plachy J, Stangassinger M, Erfle V, Schlöndorff D (2000) Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med 6:769–775. doi:10.1038/77498

    Article  PubMed  CAS  Google Scholar 

  38. Matsukura S, Kokubu F, Kurokawa M, Kawaguchi M, Ieki K, Kuga H, Odaka M, Suzuki S, Watanabe S, Homma T, Takeuchi H, Nohtomi K, Adachi K (2007) Role of RIG-I, MDA-5, and PKR on the expression of inflammatory chemokines induced by synthetic dsRNA in airway epithelial cells. Int Arch Allergy Immunol 143:80–83. doi:10.1159/000101411

    Article  PubMed  CAS  Google Scholar 

  39. Miettinen M, Sareneva T, Julkunen I, Matikainen S (2001) IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2:349–355. doi:10.1038/sj.gene.6363791

    Article  PubMed  CAS  Google Scholar 

  40. Jonjic N, Peri G, Bernasconi S, Sciacca F, Colotta F, Pelicci P, Lanfrancone L, Mantovani A (1992) Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J Exp Med 176:1165–1174 doi:10.1084/jem.176.4.1165

    Article  PubMed  CAS  Google Scholar 

  41. Enriquez J, Kliniger J, Arturo JA, Delgado M, Tobar C, Mosquera M (2002) Peritonitis in continuous ambulatory peritoneal dialysis: cytokines in peritoneal fluid and blood. Adv Perit Dial 18:177–183

    PubMed  CAS  Google Scholar 

  42. Robson RL, Witowski J, Loetscher P, Williams JD, Topley N (1998) Control of leukocyte migration across the mesothelium by IFN involves differential regulation of C-C and C-X-C chemokine production. Perit Dial Int 18:118

    Google Scholar 

  43. Banas B, Luckow B, Moller M, Klier C, Nelson PJ, Schadde E, Brigl M, Halevy D, Holthöfer H, Reinhart B, Schlöndorff D (1999) Chemokine and chemokine receptor expression in a novel human mesangial cell line. J Am Soc Nephrol 10:2314–2322

    PubMed  CAS  Google Scholar 

  44. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171:4304–4431

    PubMed  CAS  Google Scholar 

  45. Marshall-Clarke S, Downes JE, Haga IR, Bowie AG, Borrow P, Pennock JL, Grencis RK, Rothwell P (2007) Polyinosinic acid is a ligand for toll-like receptor 3. J Biol Chem 282:24759–24766. doi:10.1074/jbc.M700188200

    Article  PubMed  CAS  Google Scholar 

  46. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA (2006) Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci USA 103:8459–8464. doi:10.1073/pnas.0603082103

    Article  PubMed  CAS  Google Scholar 

  47. Mori M, Imamura Y, Maegawa H, Yoshida H, Naiki H, Fukuda M (2003) Cytology of pleural effusion associated with disseminated infection caused by varicella-zoster virus in an immunocompromised patient. A case report. Acta Cytol 47:480–484

    PubMed  Google Scholar 

  48. Jones KD, Aoki Y, Chang Y, Moore PS, Yarchoan R, Tosato G (1999) Involvement of IL-10 and viral IL-6 in the spontaneous growth of Kaposi’s sarcoma herpes virus-associated infected primary effusion lymphoma cells. Blood 94:2871–2879

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported from the Deutsche Nierenstiftung by a grant to Markus Wörnle and from the Else-Kröner-Fresenius-Stiftung by a grant to Matthias Sauter and Thomas Sitter.

Author information

Authors and Affiliations

  1. Medical Policlinic, Ludwig-Maximilians-University, Pettenkoferstrasse 8a, 80336, Munich, Germany

    Markus Wörnle, Matthias Sauter, Kathrin Kastenmüller, Andrea Ribeiro, Maximilian Roeder, Holger Schmid, Florian Krötz & Thomas Sitter

  2. Department of Surgery, Ludwig-Maximilians-University, Munich, Germany

    Thomas Mussack & Roland Ladurner

Authors
  1. Markus Wörnle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Sauter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathrin Kastenmüller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maximilian Roeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Holger Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Florian Krötz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Mussack
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roland Ladurner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Sitter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Wörnle.

Additional information

Markus Wörnle and Matthias Sauter contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wörnle, M., Sauter, M., Kastenmüller, K. et al. Novel role of toll-like receptor 3, RIG-I and MDA5 in poly (I:C) RNA-induced mesothelial inflammation. Mol Cell Biochem 322, 193–206 (2009). https://doi.org/10.1007/s11010-008-9957-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-008-9957-4

Keywords

Search

Navigation