TNF-α Affects Human Cortical Neural Progenitor Cell Differentiation through the Autocrine Secretion of Leukemia Inhibitory Factor

Proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is a crucial effector of immune responses in the brain that participates in the pathogenesis of several acute and chronic neurodegenerative disorders. Accumulating evidence has suggested that TNF-alpha negatively regulates embryonic and adult neurogenesis. However, the effect of TNF-alpha on cell fate decision in human neural progenitor cells (NPCs) has rarely been studied. Our previous studies have shown that recombinant TNF-alpha enhances astrogliogenesis and inhibits neurogenesis of human NPCs through the STAT3 (signal transducer and activator of transcription 3) pathway. In the current study, we further elucidated the specific mechanism involved in TNF-alpha-induced astrogliogenesis. We found that TNF-alpha activated STAT3 at delayed time points (6 h and 24 h), whereas conditioned medium collected from TNF-alpha-treated NPCs induced an immediate STAT3 activation. These data suggest TNF-alpha plays an indirect role on STAT3 activation and the subsequent NPC differentiation. Further, we showed that TNF-alpha induced abundant amounts of the IL-6 family cytokines, including Leukemia inhibitory factor (LIF) and Interleukin 6 (IL-6), in human NPCs. TNF-alpha-induced STAT3 phosphorylation and astrogliogenesis were abrogated by the addition of neutralizing antibody for LIF, but not for IL-6, revealing a critical role of autocrine secretion of LIF in TNF-alpha-induced STAT3 activation and astrogliogenesis. This study generates important data elucidating the role of TNF-alpha in neurogenesis and may provide insight into new therapeutic strategies for brain inflammation.