Be. Henricson et al., DISSOCIATION OF LIPOPOLYSACCHARIDE (LPS)-INDUCIBLE GENE-EXPRESSION INMURINE MACROPHAGES PRETREATED WITH SMOOTH LPS VERSUS MONOPHOSPHORYL LIPID-A, Infection and immunity, 61(6), 1993, pp. 2325-2333
Lipopolysaccharide (LPS) and the nontoxic derivative of lipid A, monop
hosphoryl lipid A (MPL), were employed to assess the relationship betw
een expression of LPS-inducible inflammatory genes and the induction o
f tolerance to LPS in murine macrophages. Both LPS and MPL induced exp
ression (as assessed by increased steady-state mRNA levels) of a panel
of seven ''early'' inflammatory genes including the tumor necrosis fa
ctor alpha (TNF-alpha), interleukin-1beta, type 2 TNF receptor (TNFR-2
), IP-10, D3, D8, and D2 genes (the last four represent LPS-inducible
early genes whose functions remain unknown). In addition, LPS and MPL
were both capable of inducing tolerance to LPS. The two stimuli differ
ed in the relative concentration required to induce various outcome me
asures, with LPS being 100- to 1,000-fold more potent on a mass concen
tration basis. Characterization of the tolerant state identified three
distinct categories of responsiveness. Two genes (IP-10 and D8) exhib
ited strong desensitization in macrophages pretreated with tolerance-i
nducing concentrations of either LPS or MPL. In macrophages rendered t
olerant by pretreatment with LPS or MPL, a second group of inducible m
RNAs (TNF-alpha, interleukin-1beta, and D3) showed moderate suppressio
n of response to secondary stimulation by LPS. The third category of i
nducible genes (TNFR-2 and D2) showed increased expression in macropha
ges pretreated with tolerance-inducing concentrations of either LPS or
MPL. All of the LPS-inducible genes examined exhibited modest superin
duction with less than tolerance-inducing concentrations of either sti
mulus, suggesting a priming effect of these adjuvants at low concentra
tion. The differential behavior of the members of this panel of endoto
xin-responsive genes thus offers insight into molecular events associa
ted with acquisition of transient tolerance to LPS.