Interleukin-1 activates a novel p54 MAP Kinase Kinase in rabbit liver

The major inflammatory cytokine interleukin-1 (IL-1) exerts pleiotropic effects during acute or chronic inflammatory disease. On a cellular level it often increases expression of genes for many proteins involved in initiating or maintaining an inflammatory process, like cytokines (IL-2, IL-6, IL-8, G-CSF, GM-CSF), adhesion molecules (ICAM-1, SLAM-1), proteinases (collagenases, stromelysin, gelatinases), cyclooxygenases, acute phase proteins and others. However the molecular mechanisms of signal transduction induced by IL-1 are poorly understood. IL-1 enhances phosphorylation of intracellular proteins, including the epidermal growth factor receptor (EGF-R) and the small heat shock protein hsp27. Accordingly, IL-1-activated protein kinases can be detected in extracts of stimulated cells. Some of these have been identified as members of the mitogen activated protein kinase (M.APK) family (1,2). As yet no consistent pattern of activation of these kinases by IL-1 has been found amongst different cell lines (1,2,3). In order to identify protein kinases which are physiologically relevant to IL-1 signalling, we injected rabbits intravenously with IL-1 and prepared extracts from their livers. Using the EGF receptor peptide T669 as a substrate, we purified two IL-1 -induced protein kinases by sequential chromatography to homogeneity and identified them as two isoforms of stress activated protein kinase (SAPK) α also called p54 MAP kinase α (4). Here we present evidence using recombinant protein kinases as substrates that IL- I also activates a novel SAPK activator (a p54 MAP Kinase Kinase) in rabbit liver.