Src-suppressed C kinase substrate (SSeCKS), a protein kinase C substrate, is a major lipopolysaccharide (LPS) response protein, regulating the inflammatory process. In the process of spinal inflammatory diseases by LPS intraspinal injection, expression of SSeCKS in the spinal cord was increased, mainly in active astrocytes and neurons. Induced SSeCKS was colabeled with terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling (an apoptosis maker) in the late inflammation processes. These results indicated that SSeCKS might correlate with the inflammatory reaction and late neurodegeneration after LPS injection. A cell type-specific action for SSeCKS was further studied within C6 cells and PC12 cells. Knockdown of SSeCKS by small-interfering RNAs (siRNAs) blocked the LPS-induced inducible nitric oxide synthase (iNOS) expression in C6 cells, while overexpression SSeCKS enhanced iNOS expression. SSeCKS is also participated in regulation of PC12 cell viability. Loss of SSeCKS rescued PC12 cell viability, and excessive SSeCKS exacerbated the cell death upon conditioned medium and tumor necrosis factor-alpha exposure. This study delineates that SSeCKS may be important for host defenses in spinal inflammation and suggests a valuable molecular mechanism by which astrocytes modify neuronal viability during pathological states.