Bacterial lipopolysacharide (LPS; endotoxin) is implicated in the pathogenesis of
acute liver disease due to the induction of tumour necrosis factor (TNF)α, a key determinant
for the outcome of acute liver failure during septic shock. Since p38 Mitogen Activated
Protein Kinases (MAPK) pathway is involved in hepatocyte apoptosis and in TNFα production,
we tested the role of MKK3 and MKK6, the two upstream kinases, in liver injury. We
found that Mkk3-/-Mkk6-/+ (MKK3/6) mice are protected against LPS induced hepatitis
because of a reduction of TNFα production.
MKK3 and MKK6 control the activation of the four p38 MAPK isoforms. In order to dissect
which isoform was involved in the protection observed, we decided to study the effect
of two inhibitors, SB203580 and BIRB796, in LPS-induced hepatitis. Whereas SB203580
pre-treatment had a hepatotoxic effect, pre-treatment with BIRB796 protected against
liver damaged and this protection was associated to significantly reduced TNFα serum
levels. These data indicates that a p38γ and p38δ have key roles in LPS-induced hepatitis.
Interestingly, this protection involves the activation of p38γ and p38δ by MKK3 and
MKK6 in macrophages and kupffer cells, but not in neutrophils. Specifically, p38γ/δ
MAPK proteins are required for the elongation of nascent TNFα protein in macrophages/Kupffer
cells.
These results identify a new regulatory pathway for TNFα production in LPS-induced
liver damage and suggest new potential cell-specific therapeutic targets for diseases
in which TNFα production is involved.
