Extracorporeal photochemotherapy induces arginase 1 in patients with graft versus host disease.
The benefits of extracorporeal photochemotherapy (ECP; psoralen and UVA exposure of blood mononuclear cells) in graft-versus-host-disease (GVHD) are well-recognized, but the mechanisms of action remain elusive. As the metabolism of l-arginine in immune cells is known to play a role in immune tolerance, we investigated the effect of ECP on arginine metabolism, and the influence of extracellular l-arginine concentration on the response to ECP in cells from patients on therapy by ECP for a GVHD and healthy donors cultured before and after ECP in the presence of different concentrations of arginine (0, 50, 100, 200 and 1000 μmol/l). At baseline arginine was not metabolized through the same pathway in patients and donors. When cells were exposed to ECP, the production of ornithine but not NO° was enhanced, while mRNA of arginase 1 was up-regulated but not INOS. In GVHD patients, increasing arginine concentration resulted in down-regulation of IFNγ and TNFα mRNA expression, whereas IL10 was up-regulated especially at physiological plasma levels (between 0 and 100 μM). Overall, our study shows that ECP orients the metabolism of arginine toward the arginase pathway together with shifting the cytokine profile toward IL-10, providing new insights into the enigmatic mechanism of action of ECP.
CHU Clermont-Ferrand, Centre Régional de Cancérologie et Thérapie Cellulaire Pédiatrique, Hôtel-Dieu, France. e_merlin@chu-clermontferrand.fr
E
E
Merlin
N
N
Goncalves-Mendes
D
D
Hannani
A
A
de la Torre
M C
MC
Farges
H
H
Laroye
F
F
Demeocq
J
J
Kanold
M P
MP
Vasson
D000293:Adolescent; D000328:Adult; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D004790:Enzyme Induction; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009952:Ornithine / Q000096:biosynthesis; D017893:Photopheresis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D009952:Ornithine; D052247:Nitric Oxide Synthase Type II; D001119:Arginase