In vitro stimulation of C3H/HeJ spleen cells and macrophages by a lipid A precursor molecule derived from Salmonella typhimurium.
C3H/HeJ mice possess a genetic lesion that renders them significantly less responsive to the biologic effects of protein-free lipopolysaccharide (LPS) preparations, and more specifically, to the lipid A region of the LPS molecule. The in vivo manifestations of this mutation are also reflected in vitro in that cells derived from this mouse strain fail to respond to LPS when compared with cells derived from fully endotoxin-responsive mouse strains. The precise nature of this gene defect has not yet been established. In this study, we have examined in vitro the biologic activities of a structurally less complex "lipid A precursor" molecule, produced by a conditionally lethal, temperature-sensitive mutant of Salmonella typhimurium. In contrast to the intact LPS or wild-type lipid A extracted from the parental strain of Salmonella typhimurium, the lipid A precursor induced a highly significant, polymyxin B-inhibitable mitogenic response in splenic cultures derived from LPS-hyporesponsive C3H/HeJ and C57BL/10ScN (nu/nu) mice. In addition, the lipid A precursor was found to stimulate cultures of C3H/HeJ macrophages to produce significant levels of both interleukin 1 (IL 1, previously referred to as "lymphocyte activating factor" or "LAF") and prostaglandins of the E series (PGE). These findings suggest the possibility that the defect in endotoxin responsiveness exhibited by C3H/HeJ mice may be related to a defect in the processing of wild-type lipid A or LPS to a suitably stimulatory form that is structurally related to the lipid A precursor molecule.
D000818:Animals; D006017:Glycolipids; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015846:Monokines; D014176:Protein Biosynthesis; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology
D006017:Glycolipids; D008050:Lipid A; D015846:Monokines; C040142:lipid A precursors, bacterial