Abstract
Tumor progression locus 2 (Tpl2)/cancer Osaka thyroid kinase is a newer member of MAP3K family that is now known for its essential role in tumor necrosis factor-aplha (TNFα) expression in macrophages, but its pro-inflammatory signaling, if any, in glia is unknown. When cultures of murine microglia and astrocytes were exposed to lipopolysaccharide, there was a rapid activation (i.e., phosphorylation) of Tpl2 in parallel to the activation of down-stream effector MAPKs, that is, extracellular signal regulated kinase (ERK), p38 MAPK and C-Jun N-terminal kinase (JNK). Pre-incubation of the cultures with a Tpl2 inhibitor selectively suppressed the activation of the primary down-stream target, that is, ERK relative to p38 MAPK and JNK. That Tpl2 activation was functionally involved in glial inflammatory response was indicated by a reduced release of the cytokines, i.e. TNFα and the expression of inducible nitric oxide synthase in the presence of the kinase inhibitor. Furthermore, over-expression of a wild-type Tpl2 construct in C-6 glia resulted in an enhanced transcriptional activation of inducible nitric oxide synthase, while transfection with a dominant negative form of Tpl-2 had the opposite effect. The findings assign an important pro-inflammatory signaling function for Tpl2 pathway in glial cells.