Skip to main content
SpringerLink
Log in

SIGIRR inhibits toll-like receptor 4, 5, 9-mediated immune responses in human airway epithelial cells

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Human airway epithelial cells (HAEC) may contribute to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) through toll-like receptors (TLRs)-mediated molecular mechanisms. TLRs exist on the surface of HAEC where binding to their cognate ligands initiates airway inflammation. Single immunoglobulin interleukin-1 receptor-related protein (SIGIRR) is a member of the toll-interleukin-1 receptor (TIR) family that can negatively modulate the immune response. We carried out studies to characterize SIGIRR modulation of TLR-mediated immune response in HAEC and to define its mechanisms of action. Following treatment with various concentrations of LPS, flagellin and CpG DNA, the levels of cognate TLRs 4, 5, and 9 were measured in the supernatants of HAEC over-expressing the SIGIRR molecule. Moreover, the interaction of the TLR adaptor myeloid differentiation factor 88 (MyD88) with SIGIRR in response to LPS-, flagellin- and CpG DNA-stimulation was examined by co-immunoprecipitation. The findings from this study revealed that overexpression of SIGIRR in HAEC stimulated by LPS, flagellin or CpG DNA resulted in attenuated production of the inflammatory mediators IL-6 and TNF-α. This attenuation was not the result of decreased expression of TLR4, 5 or 9, but rather a sequestration of MyD88 to the TLRs. In conclusion, SIGIRR can inhibit TLR4, 5, and 9-mediated immune responses in HAEC and may be a valuable therapeutic target for the prevention of ALI/ARDS.

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

Similar content being viewed by others

References

  1. Wang X, Adler KB, Erjefalt J, Bai C (2007) Airway epithelial dysfunction in the development of acute lung injury and acute respiratory distress syndrome. Expert Rev Respir Med 1:149–156

    Article  CAS  PubMed  Google Scholar 

  2. Diamond G, Legarda D, Ryan LK (2000) The innate immune response of the respiratory epithelium. Immunol Rev 173:27–38

    Article  CAS  PubMed  Google Scholar 

  3. Lee MS, Kim YJ (2007) Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem 76:447–480

    Article  CAS  PubMed  Google Scholar 

  4. Miadonna A, Gibelli S, Lorini M et al (1997) Expression of cytokine mRNA in bronchoalveolar lavage cells from atopic asthmatics before late antigen-induced reaction. Lung 175:195–209

    Article  CAS  PubMed  Google Scholar 

  5. Beutler B, Hoebe K, Georgel P, Tabeta K, Du X (2005) Genetic analysis of innate immunity: identification and function of the TIR adapter proteins. Adv Exp Med Biol 560:29–39

    Article  CAS  PubMed  Google Scholar 

  6. Kawai T, Akira S (2005) Pathogen recognition with toll-like receptors. Curr Opin Immunol 17:338–344

    Article  CAS  PubMed  Google Scholar 

  7. Yamamoto M, Sato S, Hemmi H et al (2003) TRAM is specifically involved in the toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150

    Article  CAS  PubMed  Google Scholar 

  8. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115–122

    Article  CAS  PubMed  Google Scholar 

  9. Hertzog PJ, O’Neill LA, Hamilton JA et al (2003) The interferon in TLR signaling: more than just antiviral. Trends Immunol 24:534–539

    Article  CAS  PubMed  Google Scholar 

  10. Beutler B (2004) Inferences, questions and possibilities in toll-like receptor signalling. Nature 430:257–263

    Article  CAS  PubMed  Google Scholar 

  11. Weighardt H, Holzmann B (2007) Role of toll-like receptor responses for sepsis pathogenesis. Immunobiology 212:715–722

    Article  CAS  PubMed  Google Scholar 

  12. Du X, Poltorak A, Wei Y, Beutler B et al (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw 11:362–371

    CAS  PubMed  Google Scholar 

  13. Kimbrell DA, Beutler B (2001) The evolution and genetics of innate immunity. Nat Rev Genet 2:256–267

    Article  CAS  PubMed  Google Scholar 

  14. Thomassen E, Renshaw BR, Sims JE (1999) Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1r superfamily. Cytokine 11:389–399

    Article  CAS  PubMed  Google Scholar 

  15. Polentarutti N, Rol GP, Muzio M et al (2003) Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR. Eur Cytokine Netw 14:211–218

    CAS  PubMed  Google Scholar 

  16. Wald D, Qin J, Zhao Z, Qian Y et al (2003) SIGIRR, a negative regulator of toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4:920–927

    Article  CAS  PubMed  Google Scholar 

  17. Huang X, Hazlett LD, Du W, Barrett RP (2006) SIGIRR promotes resistance against pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling. J Immunol 177:548–556

    CAS  PubMed  Google Scholar 

  18. Xiao H, Gulen MF, Qin J et al (2007) The toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26:461–475

    Article  CAS  PubMed  Google Scholar 

  19. Tsuboi N, Yoshikai Y, Matsuo S et al (2002) Roles of toll-like receptors in c-c chemokine production by renal tubular epithelial cells. J Immunol 169:2026–2033

    CAS  PubMed  Google Scholar 

  20. Qin J, Qian Y, Yao J, Grace C, Li X (2005) SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms. J Biol Chem 280:25233–25241

    Article  CAS  PubMed  Google Scholar 

  21. Granio O, Norez C, Ashbourne Excoffon KJ et al (2007) Cellular localization and activity of Ad-delivered GFP-cftr in airway epithelial and tracheal cells. Am J Respir Cell Mol Biol 37:631–639

    Article  CAS  PubMed  Google Scholar 

  22. Li Q, Zhou XD, Xu XY, Yang J (2009) Recombinant human elafin protects airway epithelium integrity during inflammation. Mol Biol Rep. doi:10.1007/s11033-009-9865-z

  23. Garlanda C, Di Liberto D, Vecchi A et al (2007) Damping excessive inflammation and tissue damage in mycobacterium tuberculosis infection by toll IL-1 receptor 8/single ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling. J Immunol 179:3119–3125

    CAS  PubMed  Google Scholar 

  24. Adib-Conquy M, Adrie C, Fitting C et al (2006) Up-regulation of MyD88s and SIGIRR, molecules inhibiting toll-like receptor signaling, in monocytes from septic patients. Crit Care Med 34:2377–2385

    Article  CAS  PubMed  Google Scholar 

  25. Garlanda C, Riva F, Polentarutti N et al (2004) Intestinal inflammation in mice deficient in TIR8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci USA 101:3522–3526

    Article  CAS  PubMed  Google Scholar 

  26. Garlanda C, Riva F, Veliz T et al (2007) Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res 67:6017–6021

    Article  CAS  PubMed  Google Scholar 

  27. Lech M, Garlanda C, Mantovani A et al (2007) Different roles of TIR8/SIGIRR on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells. Kidney Int 72:182–192

    Article  CAS  PubMed  Google Scholar 

  28. Chen Z, Ma G, Qian Q et al (2009) Toll-like receptor 8 polymorphism and coronary artery disease. Mol Biol Rep 36:1897–1901

    Article  CAS  PubMed  Google Scholar 

  29. Xu CJ, Zhang WH, Pan HF et al (2009) Association study of a single nucleotide polymorphism in the exon 2 region of toll-like receptor 9 (TLR9) gene with susceptibility to systemic lupus erythematosus among Chinese. Mol Biol Rep 36:2245–2248

    Article  CAS  PubMed  Google Scholar 

  30. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z (1997) MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837–847

    Article  CAS  PubMed  Google Scholar 

  31. Burns K, Martinon F, Esslinger C et al (1998) MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 273:12203–12209

    Article  CAS  PubMed  Google Scholar 

  32. O’Neill LA (2003) SIGIRR puts the brakes on toll-like receptors. Nat Immunol 4:823–824

    Article  PubMed  Google Scholar 

  33. Gong J, Wei T, Stark RW et al. (2009) Inhibition of toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: a computational approach. J Struct Biol. doi:10.1016/j.jsb.2009.12.007

  34. Bartfai T, Behrens MM, Gaidarova S et al (2003) A low molecular weight mimic of the toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc Natl Acad Sci USA 100:7971–7976

    Article  CAS  PubMed  Google Scholar 

  35. Ragnarsdottir B, Samuelsson M, Gustafsson MC (2007) Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J Infect Dis 196:475–484

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the technical assistance of W. Sun in confocal fluorescence microscopy. This work was supported by the National Natural Science Foundation of China (NSFC No. 30600272) and the National Natural Science Foundation of Chongqing (2008BB5121).

Author information

Authors and Affiliations

  1. Institute of Respiratory Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People’s Republic of China

    Chun Zhang, Xueling Wu & Guisheng Qian

  2. Department of Respiratory Medicine, The Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People’s Republic of China

    Yunfeng Zhao

  3. Department of Intensive Care Unit, SouthWest Hospital, Third Military Medical University, Chongqing, 400039, People’s Republic of China

    Zhaoxia Deng

Authors
  1. Chun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueling Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yunfeng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhaoxia Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guisheng Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guisheng Qian.

Additional information

Chun Zhang and Xueling Wu contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 30 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, C., Wu, X., Zhao, Y. et al. SIGIRR inhibits toll-like receptor 4, 5, 9-mediated immune responses in human airway epithelial cells. Mol Biol Rep 38, 601–609 (2011). https://doi.org/10.1007/s11033-010-0146-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-010-0146-7

Keywords

Search

Navigation