Gingival epithelial cells heterozygous for Toll-like receptor 4 polymorphisms Asp299Gly and Thr399Ile are hypo-responsive to Porphyromonas gingivalis

Kinane Denis F.

Shiba Hideki

Stathopoulou Panagiota G.

Zhao Hongli

Lappin David F.

Singh Amar

Eskan Mehmet A.

Beckers Simone

Weigel Sabine

Alpert Brian

Knudsen Thomas B.

Genes and Immunity

The Toll-like receptor (TLR4) is the major sensor for bacterial lipopolysaccharide and its two common co-segregating polymorphisms, Asp299Gly and Thr399Ile, which occur at a frequency of between 6 and 10%, have been associated with infectious diseases, LPS hypo-responsiveness and cardiovascular disease. Porphyromonas gingivalis is a Gram negative bacterium implicated in chronic periodontitis and is a known TLR4 and TLR2 agonist. We obtained two gingival epithelial cell primary cultures from subjects heterozygous for the TLR4 polymorphism Asp299Gly and compared response characteristics with similar cells from patients (four) with the wild type TLR4 genes. Cytokine responses and transcriptome profiles of gingival epithelial cell primary culture cells to TNFα challenge were similar for all primary epithelial cell cultures. P. gingivalis challenge however, gave markedly different responses for Asp299Gly heterozygous and wild-type epithelial cell cultures. The epithelial cells heterozygous for the TLR4 polymorphism Asp299Gly were functionally hypo-responsive, evidenced by differences in BD-2 mRNA expression, mRNA response profile by microarray analysis and by pro-inflammatory and chemokine cytokines at the protein and mRNA level. These findings emphasize variance in human epithelial cell TLRs, linked with Asp299Gly carriage, which results in a hypo-responsive epithelial cell phenotype less susceptible to Gram negative diseases and associated systemic conditions.

Toll-like receptors

periodontitis

epithelial cells

tissue culture

disease susceptibility

eng

Nature Publishing Group

Copyright (c) 2006 Nature Publishing Group.

[ISSN] 1466-4879

[DOI] 10.1038/sj.gene.6364282

[PMID] 16437123

[NCID] AA11474931

[DOI] http://dx.doi.org/10.1038/sj.gene.6364282