Astrocyte activation plays a pivotal role in neuroinflammation, which contributes to neuronal damage, so the inhibition of astrocyte activation may alleviate the progression of neurodegeneration. Recent studies have proved that urinary trypsin inhibitor ulinastatin could inhibit NF-kappa B activation. In our study, the inhibitory effects of ulinastatin on the production of pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-reduced primary astrocyte. Our results showed that ulinastatin significantly inhibited LPS-induced astrogliosis, which is measured by MTT and BrdU. Ulinastatin decreased the production of pro-inflammatory cytokines, such as TNF-alpha, IL-6, IL-1 beta, it significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and also increased the protein levels of IKB-alpha binded to NF-kappa B, which blocked NF-kappa B translocation to the nucleus and prevented its activity. Our results suggest that ulinastatin is able to inhibit neuroinflammation by interfering with NF-kappa B signaling. The study provides direct evidence of potential therapy methods of ulinastatin for the treatment of neuroinflammatory diseases. (C) 2015 Elsevier Inc. All rights reserved.