A pivotal role of mixed lineage kinases (MLK) in microglial and astrocyte inflammation

Abstract

CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and prevents neurodegeneration in animal models of Parkinson’s disease (PD). Glial activation may involve kinase pathways controlled by MLKs, and might contribute to the pathology of neurodegenerative diseases. Therefore, the possibility that CEP-1347 modulates the inflammatory response was explored. Indeed, the MLK inhibitor reduced cytokine production in primary cultures of human and murine microglia, in primary astrocytes, and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins, a cytokine mix or the plaque forming peptide Ab1-40. Moreover, CEP-1347 inhibited brain TNF production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in glia. The dampening of the activity of both pathways resulted in a complex pattern of inflammatory modulation as revealed by chip analysis. These data imply MLKs as important, yet unrecognized, modulators of brain inflammation, and demonstrate a novel anti-inflammatory potential of CEP-1347.