Expression of Fas ligand improves the effect of IL-4 in collagen-induced arthritis.
The present study was aimed at investigating whether the expression of Fas ligand (FasL) by CHO cells transfected with IL-4 (CHO/IL-4) or IL-10 (CHO/IL-10) genes would improve the effect of the cytokine. DBA/ 1 mice immunized with type II collagen were treated with suboptimal doses of transfected CHO cells (a single s. c. injection of 2 x 10(5) cells) around onset of arthritis. Severe collagen-induced arthritis (CIA) developed in the control groups injected with PBS, CHO /beta-galactosidase/FasL, CHO/IL-4 or CHO/IL-10 cells. In contrast, administration of CHO/IL-4/FasL, but not CHO/IL-10/FasL, cells significantly reduced the clinical severity and resulted in rapid and sustained suppressive effect. Amelioration of CIA was not due to a prolonged in vivo secretion of IL-4 since expression of FasL by CHO cells shortened the in vivo survival of the xenogeneic cells. In fact, administration of FasL(+) cells was associated with a decreased proportion of Mac1(+) neutrophils in the blood and an increased expression of myeloperoxidase at the site of engineered cell engraftment. These findings suggest that the mechanism underlying the beneficial effect of IL-4 delivered by cells expressing FasL involves the combination of the anti-inflammatory properties of IL-4 and the apoptosis of Fas(+) Mac1(+) granulocytes participating in the pathogenic process.
Guéry
L
L
INSERM U477 Université René Descartes, Paris, France.
Batteux
F
F
Bessis
N
N
Breban
M
M
Boissier
M C
MC
Fournier
C
C
Chiocchia
G
G
D000818:Animals; D001168:Arthritis / Q000517:prevention & control*; D016466:CHO Cells; D002470:Cell Survival; D003094:Collagen / Q000276:immunology*; D006224:Cricetinae; D053222:Fas Ligand Protein; D015316:Genetic Therapy; D015847:Interleukin-4 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA; D009195:Peroxidase / Q000378:metabolism
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D015847:Interleukin-4; D003094:Collagen; D009195:Peroxidase