Interferon-inducible protein (IP)-10 is a major chemokine for lymphocyte recruitment and is upregulated in inflammatory bowel diseases (IBD). Previously it was suggested that Lactobacillus paracasei (L.p) from the clinically relevant probiotic mixture VSL#3, expresses a probiotic isotype of the prtP-encoded serine protease lactocepin that mediates post-translational loss of the pro-inflammatory chemokine IP-10 in intestinal epithelial cells. The aim of the present study was to confirm this hypothesis, elucidate the underlying molecular mechanism of this effect and assess the anti-inflammatory effects of prtP-encoded lactocepin in mouse models of chronic intestinal inflammation. In summary, the present study characterizes the selective degradation of pro-inflammatory chemokines by probiotic prtP-encoded lactocepins as a protective microbial structure-function relationship in the context of chronic intestinal inflammation, suggesting development of lactocepin-based therapies as effective treatment for chemokine-mediated diseases in general.