Stimulation of spleen cells and macrophages of C3H/HeJ mice by a lipid A precursor derived from Salmonella typhimurium.

Abstract

Lipid A is that portion of the lipopolysaccharide (LPS) molecule believed to mediate most of the biologic activities associated with protein-free endotoxic preparations. C3H/HeJ mice possess a mutation at the Lps gene locus (Lpsd) that results in a state of profound hyporesponsiveness to the biologic effects of LPS (and more specifically, lipid A) in vivo. The relative unresponsiveness in vivo to LPS exhibited by these mice is reflected at a cellular level, as evidenced by a failure of many different cell types derived from the C3H/HeJ strain to respond to LPS or lipid A in vitro; this lack of response contrasts with that of cell cultures prepared from endotoxin responsive (Lpsn) mouse strains. Evidence is presented which demonstrates that a lipid A precursor molecule, produced by a mutant of Salmonella typhimurium conditionally defective in the synthesis of 3-deoxy-D-mannooctulosonic acid, stimulates mitogenesis in C3H/HeJ splenic cultures and induces cultures of C3H/HeJ macrophages to produce significant levels of the monokine interleukin-1 (IL-1; previously referred to as lymphocyte activating factor or LAF) and prostaglandins of the E series. These findings suggest the possibility that the failure of C3H/HeJ cells to respond to intact LPS or lipid A may be related to a defect in the processing of lipid A or LPS to a suitably stimulatory form, rather than to a defect in the recognition of the lipid A region.