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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0803014v1 183/2/897    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Andresen, L. Articles by Skov, S. PubMed PubMed Citation Articles by Andresen, L. Articles by Skov, S.

Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells¹

Lars Andresen^2,*, Karen Aagaard Hansen^2,*, Helle Jensen^*, Stine Falsig Pedersen, Peter Stougaard, Helle Rüsz Hansen, Jesper Jurlander^¶ and Søren Skov^3,*

^* Department of Veterinary Disease Biology, Cell and Developmental Biology, Department of Ecology, and Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Copenhagen, Denmark; and ^¶ Department of Hematology, The State Hospital, Copenhagen, Denmark

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported from the Danish Medical Research Council, the Novo Nordisk Foundation, and the A.P. Møller Foundation for Advancement of Medical Science to S.S. K.A.H. was supported by the Danish Cancer Society. H.J. was supported by the Novo Nordisk Scholarship program.

² L.A. and K.A.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Søren Skov, Laboratory of Immunology, Faculty of Life Sciences, University of Copenhagen, Stigbøjlen 7, 1870 Frederiksberg C, Denmark. E-mail address: sosk{at}life.ku.dk

⁴ Abbreviations used in this paper: MICA/B, MHC class I polypeptide-related sequence A and B; 2fDG, 2-fluoro-2-deoxy-D-glucose; 6-AN, 6-aminonicotinamide; BCECF-AM, 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester; DiO, 3,3'-dilinoleyloxacarbocyanine perchlorate; HDAC, histone deacetylase; IAA, iodoacetic acid; pH_i, intracellular pH; PI, propidium iodide; PPP, pentose phosphate pathway; RAET1G, retinoic acid early transcript 1G; SCFA, short chain fatty acid; siRNA, small interfering RNA; TCA, tricarboxylic acid; TPI, triosephosphate isomerase; ULBP1–4, UL16 binding proteins 1–4; WT, wild type.