L-carnitine, a diet component and organic cation transporter OCTN ligand, displays immunosuppressive properties and abrogates intestinal inflammation.
Allele variants in the L-carnitine (LCAR) transporters OCTN1 (SLC22A4, 1672 C --> T) and OCTN2 (SLC22A5, -207 G --> C) have been implicated in susceptibility to Crohn's disease (CD). LCAR is consumed in the diet and transported actively from the intestinal lumen via the organic cation transporter OCTN2. While recognized mainly for its role in fatty acid metabolism, several lines of evidence suggest that LCAR may also display immunosuppressive properties. This study sought to investigate the immunomodulatory capacity of LCAR on antigen-presenting cell (APC) and CD4+ T cell function by examining cytokine production and the expression of activation markers in LCAR-supplemented and deficient cell culture systems. The therapeutic efficacy of its systemic administration was then evaluated during the establishment of colonic inflammation in vivo. LCAR treatment significantly inhibited both APC and CD4+ T cell function, as assessed by the expression of classical activation markers, proliferation and cytokine production. Carnitine deficiency resulted in the hyperactivation of CD4+ T cells and enhanced cytokine production. In vivo, protection from trinitrobenzene sulphonic acid colitis was observed in LCAR-treated mice and was attributed to the abrogation of both innate [interleukin (IL)-1beta and IL-6 production] and adaptive (T cell proliferation in draining lymph nodes) immune responses. LCAR therapy may therefore represent a novel alternative therapeutic strategy and highlights the role of diet in CD.
Fortin
G
G
Department of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada. genevieve.r.fortin@mail.mcgill.ca
Yurchenko
K
K
Collette
C
C
Rubio
M
M
Villani
A-C
AC
Bitton
A
A
Sarfati
M
M
Franchimont
D
D
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002331:Carnitine / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D027701:Organic Cation Transport Proteins / Q000502:physiology; D000074058:Solute Carrier Family 22 Member 5; D013154:Spleen / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid
D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D027701:Organic Cation Transport Proteins; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D014302:Trinitrobenzenesulfonic Acid; D002331:Carnitine