Salivary epithelial cells from Sjogren's syndrome patients are highly sensitive to anoikis induced by TLR-3 ligation

J Autoimmun. 2010 Nov;35(3):212-8. doi: 10.1016/j.jaut.2010.06.010. Epub 2010 Aug 3.


In certain types of cells, Toll-like receptor-3 (TLR-3) ligation by viral dsRNA induces apoptotic death, likely engaged into the elimination of virus-infected cells. We have previously shown that TLR-3 ligation on cultured non-neoplastic salivary gland epithelial cells (SGEC) with polyI:C (a synthetic analogue of viral dsRNA) results in the induction of surface immunoactive molecules, however, the pro-apoptotic effect of such signaling has not been addressed. In this study, polyI:C-treated SGEC were found to suffer severe detachment from substratum and subsequent apoptosis, a phenomenon suggestive of anoikis or anoikia (detachment-induced apoptosis). PolyI:C-induced anoikis in SGEC was associated with the upregulation of the pro-apoptotic Bmf, BimEL and Bax and the down-regulation of the pro-survival Bcl-2 (real-time PCR analyses). Finally, the comparative analysis of SGEC lines derived from primary Sjogren's syndrome (SS) patients (SS-SGEC) and non-SS controls had revealed that SS-SGEC are particularly susceptible to TLR-3-induced anoikis, as it was triggered by suboptimally low concentrations of polyI:C. This finding correlated with significantly higher constitutive surface TLR-3 expression by SS-SGEC, a feature indicative of their intrinsic activation status. In conclusion, TLR-3 signaling pathway in the salivary epithelium appears to extend beyond the induction of innate immune responses and to involve the activation of programmed-cell death via anoikis. In the same context, the increased vulnerability of SS-SGEC to the injurious effect of TLR-3 ligation is likely associated with the intrinsic activation processes that apparently operate in the epithelia of SS patients, and a feature of key pathogenetic importance for the disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics
  • Anoikis* / drug effects
  • Anoikis* / immunology
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Bcl-2-Like Protein 11
  • Cell Adhesion / drug effects
  • Cell Adhesion / immunology
  • Cell Line
  • Epithelial Cells / drug effects*
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Humans
  • Immunity, Innate
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Poly I-C / pharmacology
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Salivary Glands / pathology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sjogren's Syndrome / immunology*
  • Sjogren's Syndrome / pathology
  • Sjogren's Syndrome / physiopathology
  • Toll-Like Receptor 3 / agonists
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism*
  • bcl-2-Associated X Protein / biosynthesis
  • bcl-2-Associated X Protein / genetics


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • BMF protein, human
  • Bcl-2-Like Protein 11
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • bcl-2-Associated X Protein
  • Interferon-beta
  • Poly I-C