TY - JOUR

T1 - Propionic acid secreted from propionibacteria induces NKG2D ligand expression on human-activated T lymphocytes and cancer cells

AU - Andresen, Lars

AU - Hansen, Karen Aagaard

AU - Jensen, Helle

AU - Pedersen, Stine Helene Falsig

AU - Stougaard, Peter

AU - Hansen, Helle Rüsz

AU - Jurlander, Jesper

AU - Skov, Søren

N1 - Keywords: Bacteria; Calcium; Cell Line, Tumor; Hematologic Neoplasms; Histocompatibility Antigens Class I; Humans; Jurkat Cells; Ligands; Lymphocyte Activation; NK Cell Lectin-Like Receptor Subfamily K; Promoter Regions, Genetic; Propionic Acids; T-Lymphocytes; Transcriptional Activation

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Bacteria

KW - Calcium

KW - Cell Line, Tumor

KW - Hematologic Neoplasms

KW - Histocompatibility Antigens Class I

KW - Humans

KW - Jurkat Cells

KW - Ligands

KW - Lymphocyte Activation

KW - NK Cell Lectin-Like Receptor Subfamily K

KW - Promoter Regions, Genetic

KW - Propionic Acids

KW - T-Lymphocytes

KW - Transcriptional Activation

U2 - 10.4049/jimmunol.0803014

DO - 10.4049/jimmunol.0803014

M3 - Journal article

C2 - 19553547

VL - 183

SP - 897

EP - 906

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -