Skip to main content
Log in

Expression and Functional Analysis of Toll-Like Receptors of Peripheral Blood Cells in Asthmatic Patients: Implication for Immunopathological Mechanism in Asthma

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Background

We investigated the expression profile of toll-like receptors (TLRs) and TLR ligand-activated production profile of asthma-related inflammatory cytokines in asthmatic patients. The expression of TLR1–8 on monocytes, CD4+ T helper lymphocytes, CD8+ T cytotoxic lymphocytes, CD19+ B lymphocytes, and dendritic cells, and ex vivo production of cytokines from peripheral blood mononuclear cells activated by TLR ligands were measured by flow cytometry.

Discussion

Ex vivo productions of TNF-α, IL-10, and IL-1β by TLR4 and TLR5 ligand LPS and flagellin were significantly lower in asthmatic patients (all P < 0.05). Expression of TLR4 and TLR5 was also found to be significantly lower in asthmatic patients when compared to that of control subjects (all P < 0.05). Therefore, the decreased activation of TLR4 and TLR5 in asthmatic patients might contribute to the immunopathological mechanisms of asthma by reducing the release of Th1 and anti-inflammatory cytokines.

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

Access this article

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

Similar content being viewed by others

References

  1. Yssel H, Groux H. Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases. Int Arch Allergy Immunol. 2000. 121:10–8. doi:10.1159/000024292.

    Article  PubMed  CAS  Google Scholar 

  2. Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax. 2000. 55(Suppl 1):S2–10. doi:10.1136/thorax.55.suppl_1.S2.

    Article  PubMed  Google Scholar 

  3. Feleszko W, Jaworska J, Hamelmann E. Toll-like receptors—novel targets in allergic airway disease (probiotics, friends and relatives). Eur J Pharmacol. 2006. 533:308–18. doi:10.1016/j.ejphar.2005.12.062.

    Article  PubMed  CAS  Google Scholar 

  4. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002. 347:911–20. doi:10.1056/NEJMra020100.

    Article  PubMed  Google Scholar 

  5. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol. 2001. 1:69–75. doi:10.1038/35095579.

    Article  PubMed  CAS  Google Scholar 

  6. Dahl ME, Dabbagh K, Liggitt D, Kim S, Lewis DB. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat Immunol. 2004. 5:337–43. doi:10.1038/ni1041.

    Article  PubMed  CAS  Google Scholar 

  7. Camateros P, Moisan J, Hénault J, De Sanctis J, Skamene E, Radzioch D. Toll-like receptors, cytokines and the immunotherapeutics of asthma. Curr Pharm Des. 2006. 12:2365–74. doi:10.2174/138161206777698918.

    Article  PubMed  CAS  Google Scholar 

  8. Bauer S, Hangel D, Yu P. Immunobiology of toll-like receptors in allergic disease. Immunobiology. 2007. 212:521–33. doi:10.1016/j.imbio.2007.03.011.

    Article  PubMed  CAS  Google Scholar 

  9. Hopkins PA, Sriskandan S. Mammalian Toll-like receptors: to immunity and beyond. Clin Exp Immunol. 2005. 140:395–407. doi:10.1111/j.1365-2249.2005.02801.x.

    Article  PubMed  CAS  Google Scholar 

  10. Schroder NW, Maurer M. The role of innate immunity in asthma: leads and lessons from mouse models. Allergy. 2007. 62:579–90. doi:10.1111/j.1398-9995.2007.01386.x.

    Article  PubMed  CAS  Google Scholar 

  11. Sukkar MB, Xie S, Khorasani NM, Kon OM, Stanbridge R, Issa R, et al. Toll-like receptor 2, 3, and 4 expression and function in human airway smooth muscle. J Allergy Clin Immunol. 2006. 118:641–8. doi:10.1016/j.jaci.2006.05.013.

    Article  PubMed  CAS  Google Scholar 

  12. O’Neill LA. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol. 2006. 18:3–9. doi:10.1016/j.coi.2005.11.012.

    Article  PubMed  CAS  Google Scholar 

  13. Palazzo M, Gariboldi S, Zanobbio L, Dusio GF, Selleri S, Bedoni M, et al. Cross-talk among Toll-like receptors and their ligands. Int Immunol. 2008. 20:709–18. doi:10.1093/intimm/dxn027.

    Article  PubMed  CAS  Google Scholar 

  14. American Thoracic Society. Guidelines for the evaluation of impairment/disability in patients with asthma. Am Rev Respir Dis. 1993;147:1056–61.

    Google Scholar 

  15. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med. 1995;152:1107–36.

    Google Scholar 

  16. Lam KK, Pang SC, Allan WG, Hill LE, Snell NJ, Fayers PM, et al. Predictive nomograms for forced expiratory volume, forced vital capacity, and peak expiratory flow rate, in Chinese adults and children. Br J Dis Chest. 1983;77:390–6.

    Article  PubMed  CAS  Google Scholar 

  17. Bethesda, MD. National Heart, Blood, and Lung Institute. Global strategy for asthma management and prevention: WHO/NHLBI workshop report. National Heart, Lung, and Blood Institute, Publication No. 95-3659, 1995

  18. Bethesda MD. National Asthma Education and Prevention Program. Expert panel report 2: Guidelines for the management of asthma. National Institutes of Health, Publication No. 97-4051, 1997

  19. Wong CK, Cheung PF, Ip WK, Lam CW. Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. Am J Respir Cell Mol Biol. 2007. 37:85–96. doi:10.1165/rcmb.2006-0457OC.

    Article  PubMed  CAS  Google Scholar 

  20. Gon Y. Toll-like receptors and airway inflammation. Allergol Int. 2008. 57:33–7. doi:10.2332/allergolint.R-07-157.

    Article  PubMed  CAS  Google Scholar 

  21. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004. 5:987–95. doi:10.1038/ni1112.

    Article  PubMed  CAS  Google Scholar 

  22. Lauener RP, Birchler T, Adamski J, Braun-Fahrländer C, Bufe A, Herz U, et al. ALEX study group: expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet. 2002. 360:465–6. doi:10.1016/S0140-6736(02)09641-1.

    Article  PubMed  CAS  Google Scholar 

  23. Re F, Strominger JL. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J Immunol. 2004;173:7548–55.

    PubMed  CAS  Google Scholar 

  24. Hawrylowicz CM. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med. 2005. 202:1459–63. doi:10.1084/jem.20052211.

    Article  PubMed  CAS  Google Scholar 

  25. Hawrylowicz CM, O’Garra A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol. 2005. 5:271–83. doi:10.1038/nri1589.

    Article  PubMed  CAS  Google Scholar 

  26. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147:3815–22.

    PubMed  CAS  Google Scholar 

  27. Agrawal S, Agrawal A, Doughty D, Gerwitz A, Blenis J, Van Dyke T, et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol. 2003;171:4984–9.

    PubMed  CAS  Google Scholar 

  28. Didierlaurent A, Ferrero I, Otten LA, Dubois B, Reinhardt M, Carlsen H, et al. Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response. J Immunol. 2004;172:6922–30.

    PubMed  CAS  Google Scholar 

  29. Cheung PF, Wong CK, Ip WK, Lam CW. FAK-mediated activation of ERK for eosinophil migration: a novel mechanism for infection-induced allergic inflammation. Int Immunol. 2008. 20:353–63. doi:10.1093/intimm/dxm146.

    Article  PubMed  CAS  Google Scholar 

  30. Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol. 2008. 8:193–204. doi:10.1038/nri2275.

    Article  PubMed  CAS  Google Scholar 

  31. Kadowaki N. Dendritic cells: a conductor of T cell differentiation. Allergol Int. 2007. 56:193–9. doi:10.2332/allergolint.R-07-146.

    Article  PubMed  CAS  Google Scholar 

  32. Semnani RT, Venugopal PG, Leifer CA, Mostböck S, Sabzevari H, Nutman TB. Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites. Blood. 2008. 112:1290–8. doi:10.1182/blood-2008-04-149856.

    Article  PubMed  CAS  Google Scholar 

  33. Kline JN, Waldschmidt TJ, Businga TR, Lemish JE, Weinstock JV, Thorne PS, et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol. 1998;160:2555–9.

    PubMed  CAS  Google Scholar 

  34. Kline JN, Krieg AM, Waldschmidt TJ, Ballas ZK, Jain V, Businga TR. CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma. J Allergy Clin Immunol. 1999. 104:1258–64. doi:10.1016/S0091-6749(99)70022-9.

    Article  PubMed  CAS  Google Scholar 

  35. Bohle B, Jahn-Schmid B, Maurer D, Kraft D, Ebner C. Oligodeoxynucleotides containing CpG motifs induce IL-12, IL-18 and IFN-gamma production in cells from allergic individuals and inhibit IgE synthesis in vitro. Eur J Immunol. 1999. 29:2344–53. doi:10.1002/(SICI)1521-4141(199907)29:07<2344::AID-IMMU2344>3.0.CO;2-R.

    Article  PubMed  CAS  Google Scholar 

  36. Persson CG, Erjefält JS, Korsgren M, Sundler F. The mouse trap. Trends Pharmacol Sci. 1997;18:465–7.

    PubMed  CAS  Google Scholar 

  37. Schleimer RP. Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium. Proc Am Thorac Soc. 2004. 1:222–30. doi:10.1513/pats.200402-018MS.

    Article  PubMed  CAS  Google Scholar 

  38. Barrat FJ, Coffman RL. Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol Rev. 2008. 223:271–83. doi:10.1111/j.1600-065X.2008.00630.x.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christopher W. K. Lam.

Additional information

Samantha W. M. Lun and C. K. Wong contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lun, S.W.M., Wong, C.K., Ko, F.W.S. et al. Expression and Functional Analysis of Toll-Like Receptors of Peripheral Blood Cells in Asthmatic Patients: Implication for Immunopathological Mechanism in Asthma. J Clin Immunol 29, 330–342 (2009). https://doi.org/10.1007/s10875-008-9269-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-008-9269-1

Keywords

Navigation