Induction of proinflammatory mediators requires activation of the TRAF, NIK, IKK and NF-κB signal transduction pathway in astrocytes infected with Escherichia coli

Escherichia coli is associated with inflammation in the brain. To investigate whether astrocytes are involved in E. coli-induced inflammation, we assessed the levels of expression of proinflammatory mediators produced by E. coli-infected astrocytes. E. coli infection in primary human astrocytes and cell lines increased expression of the CXC chemokine IL-8/GRO-alpha, the CC chemokine MCP-1, TNF-alpha, and iNOS. E. coli infection activated p65/p50 heterodimeric NF-kappa B and concurrently decreased the signals of I kappa B alpha. Blocking the NF-kappa B signals by I kappa B alpha-superrepressor-containing retrovirus or antisense p50 oligonucleotide transfection resulted in down-regulation of expression of the proinflammatory mediators. Furthermore, superrepressors of I kappa B alpha, I kappa B kinase (IKK) or NF-kappa B inducing kinase (NIK) inhibited the up-regulated expression of the downstream target genes of NF-kappa B such as IL-8 and MCP-1, and superrepressors of TNF receptor-associated factor (TRAF)2 and TRAF5 also inhibited expression of the E. coli-induced target genes of NF-kappa B. These results indicate that proinflammatory mediators such as the CXC chemokine IL-8/GRO-alpha, the CC chemokine MCP-1, TNF-alpha, and iNOS can be expressed in E. coli-infected astrocytes via an NF-kappa B pathway, suggesting that these mediators may contribute to inflammation in the brain, including infiltration of inflammatory cells.