Exp Clin Endocrinol Diabetes 2012; 120 - A8
DOI: 10.1055/s-0032-1330802

p38γ/δ MAPKs control TNFα translation in acute hepatitis

B González-Terán 1, JR Cortés 1, E Manieri 1, 2, N Matesanz 1, A Verdugo 1, 2, ME Rodríguez 1, A González-Rodríguez 3, A Valverde 3, P Martín 1, RJ Davis 4, G Sabio 1
  • 1Department of Vascular Biology and Inflammation, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain
  • 2Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, 28049 Madrid, Spain
  • 3Institute of Biomedicine Alberto Sols (CSIC/UAM), 28029 Madrid, Spain
  • 4Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

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.