Nitric oxide inhibits T cell adhesion and migration by down-regulation of beta1-integrin expression in immunologically liver-injured mice.
Our previous study has reported that nitric oxide (NO) exerts a protective role in immunologically liver-injured mice induced by delayed-type hypersensitivity to picryl chloride. To explore the mechanism of the protection, we have now examined the effect of NO on T cell adhesion and migration. First, we isolated hepatocytes and nonparenchymal cells from the liver-injured mice and separated the nonparenchymal cells into Kupffer cell-enriched and lymphocyte-enriched populations. When these hepatocytes or the fractions of nonparenchymal cells were co-cultured with spleen T cells of the liver-injured mice in a Transwell system, the adhesive potential of the T cells was significantly inhibited in the presence of hepatocytes or the Kupffer cell-enriched population but not the lymphocyte-enriched population of nonparenchymal cells. This effect was dependent on NO production. The NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) could reverse this inhibition of cell adhesion and also decrease NO production. To confirm this effect of NO on T cells, we further examined the role of exogenous or endogenous NO on the adhesive activity of the Jurkat T cell line. As a result, the NO donor, S-nitroso-N-acetyl penicillamine (SNAP) caused a dose-dependent inhibition of the adhesion of Jurkat T cells. Furthermore, the binding ability of Jurkat T cells to collagen decreased gradually after co-incubation with macrophages stimulated by LPS+IFN-gamma, an effect which correlated well with the increasing NO level in the medium. Such opposite changes in cell adhesion and in NO production were also markedly reversed by L-NMMA. Moreover, treatment with SNAP reduced adhesion, transmigration, matrix metalloproteinase-9 production and beta1-integrin expression of spleen T cells of the liver-injured mice. Taken together, these findings suggest that NO can function as a down-regulator of T cell mobility, which might be one of the mechanisms by which NO exerts its protective effect in T cell-mediated liver injury.
Sun
Yang
Y
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
Liu
Jianli
J
Qian
Feng
F
Xu
Qiang
Q
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000473:pathology; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D019693:Hepatitis, Autoimmune / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000473:pathology; D019012:Integrin beta1 / Q000096:biosynthesis*; D019169:Jurkat Cells; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D019012:Integrin beta1; D009573:Nitrites; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase