Propionic acid secreted from propionibacteria induces NKG2D ligand expression on human-activated T lymphocytes and cancer cells.
We found that propionic acid secreted from propionibacteria induces expression of the NKG2D ligands MICA/B on activated T lymphocytes and different cancer cells, without affecting MICA/B expression on resting peripheral blood cells. Growth supernatant from propionibacteria or propionate alone could directly stimulate functional MICA/B surface expression and MICA promoter activity by a mechanism dependent on intracellular calcium. Deletion and point mutations further demonstrated that a GC-box motif around -110 from the MICA transcription start site is essential for propionate-mediated MICA promoter activity. Other short-chain fatty acids such as lactate, acetate, and butyrate could also induce MICA/B expression. We observed a striking difference in the molecular signaling pathways that regulate MICA/B. A functional glycolytic pathway was essential for MICA/B expression after exposure to propionate and CMV. In contrast, compounds with histone deacetylase-inhibitory activity such as butyrate and FR901228 stimulated MICA/B expression through a pathway that was not affected by inhibition of glycolysis, clearly suggesting that MICA/B is regulated through different molecular mechanisms. We propose that propionate, produced either by bacteria or during cellular metabolism, has significant immunoregulatory function and may be cancer prophylactic.
Andresen
Lars
L
Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
Hansen
Karen Aagaard
KA
Jensen
Helle
H
Pedersen
Stine Falsig
SF
Stougaard
Peter
P
Hansen
Helle Rüsz
HR
Jurlander
Jesper
J
Skov
Søren
S
D001419:Bacteria / Q000378:metabolism*; D002118:Calcium; D045744:Cell Line, Tumor; D019337:Hematologic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics; D011401:Promoter Regions, Genetic; D011422:Propionates / Q000378:metabolism* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011422:Propionates; C029658:propionic acid; D002118:Calcium