title: Augmented macrophage PGE2 production following exposure to dimethylnitrosamine in vivo: relevance to suppressed T cell responses.
abstract: Previous efforts from our laboratory have investigated the mechanisms responsible for dimethylnitrosamine (DMN)-induced suppression of T cell responses. These studies suggested that such changes in T cell activity were most likely to be due to alterations in the down-regulatory signals controlling T cell activation. Accordingly, the production of PGE2, a potent inhibitor of T cell activation, was examined in macrophages obtained from animals exposed to either DMN or vehicle in vivo. The production of PGE2 was determined in macrophages representing various stages of activation (responsive, primed and fully activated) and various stages of differentiation (CSF-1-derived or GM-CSF-derived macrophages). All peritoneal macrophages obtained from DMN-exposed animals demonstrated enhanced production of PGE2 following stimulation with either endotoxin or IFN-gamma as compared to macrophages obtained from vehicle-exposed macrophages. Moreover, the enhanced levels of PGE2 were due to increased PGE2 production rather than to shifts in the kinetics of PGE2 production and utilization. CSF-1- and GM-CSF-induced bone-marrow-derived macrophages (BMDM) produced minimal levels of PGE2, regardless of the in vitro stimulation of cells obtained from either vehicle or DMN treatment groups. Spleen cells obtained from DMN-exposed animals produced significantly higher amounts of PGE2 following endotoxin stimulation compared to control splenocytes. Splenocytes from DMN-exposed animals also demonstrated a suppressed proliferative response to the mitogen Con A. However, when splenocytes from DMN-exposed animals were co-cultured with indomethacin they demonstrated Con A-stimulated proliferative responses similar to the responses of vehicle control splenocytes. These results demonstrate that DMN exposure results in increased PGE2 production by macrophages and that this increase in PGE2 production may be responsible for suppressed T cell responses observed in DMN-exposed animals.
authors: Department of Animal Sciences, University of Illinois, Urbana 61801.
authors: M J
authors: MJ
authors: Myers
authors: W P
authors: WP
authors: Hanafin
authors: L B
authors: LB
authors: Schook
mesh_terms: D000818:Animals; D004128:Dimethylnitrosamine / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D007166:Immunosuppressive Agents; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D008934:Mitogens; D015232:Dinoprostone; D004128:Dimethylnitrosamine