Lung fibroblasts inhibit activation-induced death of T cells through PGE(2)-dependent mechanisms.
Activation-induced cell death (AICD) is a regulatory mechanism eliminating excess activated T cells, mainly through a Fas/Fas ligand-dependent mechanism. The goal of this study was to determine whether mouse primary lung fibroblasts are capable of modulating AICD. Using T cell hybridoma DO11.10, we found that fibroblasts in coculture rescue T cells from AICD. Fibroblast-conditioned medium (FCM) also inhibited apoptosis of T cells activated with immobilized anti-CD3 antibody. The effects of lung fibroblasts are mediated, in part, by secreted prostaglandin E(2) (PGE(2)) because treatment of fibroblasts with indomethacin decreased antiapoptotic activity of FCM. Addition of exogenous PGE(2) to FCM from fibroblast cultures treated with indomethacin restored the inhibitory activity of FCM. Expression of Fas receptor and Fas ligand by anti-CD3-activated DO11.10 cells was not affected by PGE(2). However, the same concentrations of PGE(2) significantly downregulated activation of caspase-8 and caspase-3. These results demonstrate that lung fibroblasts inhibit the AICD of T cells by secreting PGE(2), which downregulates caspase activation and apoptosis.
Yarovinsky
T O
TO
Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA. timur-yarovinsky@uiowa.edu
Hunninghake
G W
GW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry; D015232:Dinoprostone / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D008168:Lung / Q000166:cytology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008863:Microspheres; D013601:T-Lymphocytes / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D017077:Culture Media, Conditioned; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D020169:Caspases; D015232:Dinoprostone