Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

The pathological consequences of endotoxic shock are attributed to the damaging effects of
high levels of TNF- , IL-6 and IL-1 induced by LPS. Since these three cytokines were
elevated in MKP-1 -/- mice, the question was asked whether MKP-1 has a role to play in the
mortality induced by toxic shock. MKP-1 +/+ and MKP-1 -/- mice were injected i.v with two
doses of LPS and survival was monitored over 48 hours. Administration of 10 mg/kg LPS
resulted in 100% mortality in MKP-1 -/- by 18 hr, whereas wild type mice died between 24
and 48 hr. At the lower dose of 2.5 mg/kg LPS, all the MKP-1 -/died
within 24 hr whereas
wild type mice survived significantly longer (Fig 6.4). This suggests that MKP-1 plays a
distinct role in controlling the innate inflammatory response following endotoxic shock and
in the absence of MKP-1, elevated levels of pro-inflammatory cytokines have significant
detrimental effects on mortality.
%Survival
100
80
60
40
20
10mg/kg 2.5mg/kg
MKP-1 +/+
MKP-1 -/-
0
0 4 7 18 26 32 48
Time After LPS Injection (Hours)
Fig 6.4. MKP-1 -/- mice are hyper-responsive to endotoxic shock in vivo. MKP-1 +/+ (solid line) and
MKP-1 -/mice
(dotted line) were injected i.p with either 10 mg/kg or 2.5mg/kg LPS and survival was
monitored up to 50 hours. Both treatments resulted in significant differences between groups, p=0.008
and p=0.004 for 10 mg/kg and 2.5 mg/kg respectively, log-rank (Mantel-Cox) test, n=5.
%Survival
225
100
80
60
40
20
MKP-1 +/+
MKP-1 -/-
0
0 18 24 32 44 50
Time After LPS Injection (Hours)