MEP1A, which encodes the α subunit of
meprin metalloproteinases, is a susceptibility gene for
inflammatory bowel disease (IBD), and decreased intestinal
meprin-α expression is associated with enhanced IBD in humans. Mice lacking
meprin α (α knockout, αKO) have more severe
colitis induced by
dextran sulfate sodium (DSS) than wild-type (WT) mice, indicating an anti-inflammatory role for
meprin A. Previous studies and those herein indicate the
meprin B has proinflammatory activities. Therefore, mice lacking both
meprin A and B (dKO mice) were generated to determine how their combined absence alters the inflammatory response to DSS. Unchallenged dKO mice grow and reproduce normally and have no obvious abnormal phenotype, except for a slightly elevated
plasma albumin in both males and females and a lower urine
creatinine level in dKO males. Upon
oral administration of 3.5% DSS, the dKO mice have more severe
colitis than the WT and βKO mice but significantly less than the αKO mice. The dKO mice lose more weight and have elevated MPO and
IL-6 activities in the colon compared with WT mice. Systemic
inflammation, monitored by plasma
nitric oxide levels, is absent in DSS-treated dKO mice, unlike WT mice. The severity of experimental IBD in dKO mice is intermediate between αKO and WT mice. The data indicate that the absence of
meprin A aggravates chronic
inflammation and the lack of
meprin B affords some protection from injury. Manipulation of the expression of
meprin gene products may have therapeutic potential.