Rescue of TNFα inhibited neuronal cells by IGF-1 involves akt and c-jun N-terminal kinases

Abstract

<jats:title>Abstract</jats:title><jats:p>Proinflammatory cytokines, especially tumor necrosis factor α (TNFα), is a pleiotropic mediator of a diverse array of physiologic and neurologic functions and is upregulated during various inflammatory and neurodegenerative diseases. A common survival response during such situations is the increased expression of the hormone insulin‐like growth factor 1 (IGF‐1). Although it was thought previously that the mechanisms of TNFα and IGF‐1 action were unrelated, it has been shown that low doses of TNFα can inhibit the survival effects of IGF‐1 in mouse cerebellar granule neurons. We used a neuronal cell line SH‐SY5Y, which underwent apoptosis in response to TNFα and this process could be reversed substantially by IGF‐1. Crosstalk between signaling pathways of these two factors was found at various points downstream of their signal transduction. To determine the mechanisms of IGF‐1‐mediated rescue, we looked at the MAP kinases, which are known to be involved in IGF‐1 as well as TNFα signaling. The c‐Jun N‐terminal kinase pathway, which is known normally to promote cell death, was found to actually promote survival of TNFα‐mediated cell death. Inhibiting the c‐Jun survival pathway completely reversed the rescue mediated by IGF‐1. In addition, the Akt pathway played an equally important role in this rescue. © 2004 Wiley‐Liss, Inc.</jats:p>