title: Induction of leukotriene production before antigen challenge enhances antibody affinity in genetically selected mice.
abstract: Mice genetically selected for their incapacity to produce high-affinity antibody to protein antigens in adjuvant (nonmaturing (NM) mice) were treated with indomethacin, an inhibitor of the cyclooxygenase pathway of arachidonic acid metabolism. Pretreatment with indomethacin significantly enhanced the affinity of antibodies produced 21 days after immunization with human serum albumin (HSA). Blockage of the cyclooxygenase pathway in this way was shown to induce the production of leukotrienes via the lipoxygenase pathway. The production of leukotrienes may well be responsible for the enhanced antibody affinity, since blockage of the lipoxygenase pathway in addition to the cyclooxygenase pathway reversed the effect. In an attempt to elucidate the mechanisms involved, IL-1 production and Ia expression by macrophages were examined. Ia expression by peritoneal cells from untreated NM mice was significantly lower than that by their high-affinity-producing counterparts 3 days after immunization. Indomethacin pretreatment raised inducible Ia antigen levels on macrophages of NM mice to those seen on cells from untreated high-affinity mice. Indomethacin treatment alone induced the production of IL-1 by macrophages in NM mice. However, 3 days after immunization and the withdrawal of indomethacin in NM mice, IL-1 production was significantly lower than the response of NM mice given antigen alone, suggestive of the induction of a feedback mechanism. Thus indomethacin pretreatment results in a cascade of events in macrophages which produce a decrease in IL-1 production and an increase in inducible Ia expression 3 days after antigen challenge.
authors.affiliation: London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010640:Phenothiazines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D015289:Leukotrienes; D010640:Phenothiazines; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; D015232:Dinoprostone; D007213:Indomethacin