concanamycin-a and Hepatitis--Autoimmune

Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA).. Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.

Topics: Animals; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Galactosylceramides; Hepatitis, Autoimmune; Immunohistochemistry; Macrolides; Male; Mice; Mice, Inbred C57BL; PPAR alpha; Real-Time Polymerase Chain Reaction; T-Lymphocytes

Adenine nucleotides induce danger signals in T cells via purinergic receptors, raising the question whether they exert similar effects on innate immunity. Here we show that micromolar concentrations of nicotinamide adenine dinucleotide (NAD) induce a rapid increase of annexin V staining in NKT cells in vitro, a response that requires expression of P2X(7)Rs. Consistent with this result, treatment of mice with NAD causes a temporary decrease of NKT cells in the liver and protects from Con A- and alpha-galactosylceramide-induced hepatitis, both of which require functional NKT cells. Resistance to liver injury is associated with decreased cytokine production by NKT cells in NAD-treated mice. In contrast, when NAD is injected into Con A- or alpha-galactosylceramide-primed mice, liver injury is exacerbated and cytokine production by NKT cells is increased. This effect is caused by P2X(7)R-mediated stimulation of activated NKT cells. In agreement, mice lacking P2X(7)Rs on lymphocytes suffer reduced liver injury, and animals lacking ADP-ribosyltransferase, the enzyme that uses NAD to attach ADP-ribosyl groups to cell surfaces, are also resistant to Con A-induced hepatitis. These results prompt the conclusion that engagement of P2X(7)Rs on NKT cells inhibits naive, while stimulating activated cells, resulting in suppression or stimulation of autoimmune hepatitis.

Topics: Animals; Annexin A5; Cells, Cultured; Cytokines; Female; Hepatitis, Autoimmune; Killer Cells, Natural; Liver; Lymphocyte Activation; Macrolides; Mice; Mice, Knockout; NAD; Receptors, Purinergic P2; Receptors, Purinergic P2X7; T-Lymphocytes, Regulatory