Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease

Abstract

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.

Metalloproteases meprin α and meprin β are C- and N-procollagen proteinases important for collagen assembly and tensile strength

“…Notably, this specificity for negatively charged amino acid residues in the P1′ site is also characteristic of two other members of the astacin family, meprin α and meprin β (13). Meprin proteases are expressed in a range of tissues, where they activate or release growth factors and other biologically active peptides, and are involved in immunological and neuropathological processes, angiogenesis, and matrix remodeling (14)(15)(16)(17)(18)(19)(20).…”

The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase

“…Meprin-␣ displayed proangiogenic properties in cell culture settings and in animal models (27,38). Furthermore, meprin-␣ showed anti-inflammatory properties in human patients with ulcerative colitis and in animal models of inflammatory bowel disease (3,4). Ac-SDKP, the product of T␤4 hydrolysis by meprin-␣ and POP, shares very similar properties with meprin-␣.…”

“…These peptides are the expected products of the T␤4 hydrolysis at the predicted meprin-␣ cleavage sites at E 21 -T 22 and E 24 -K 25 (41). In addition, data from mass spectrometry revealed two new putative cleavage sites at D 13 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] ; mass: 2,279.20 Da). This is consistent with the specificity of the active site of meprin-␣, which prefers acidic amino acids at positions near and adjacent to its cleavage site (20,21).…”

Post-transcriptional Regulation of Meprin α by the RNA-binding Proteins Hu Antigen R (HuR) and Tristetraprolin (TTP)

“…Thus, meprins have the potential to modulate the immune response by generation of either active or inactive protein fragments (1,13). Dysregulation and abnormal meprin expression have been implicated in urinary tract infection, kidney disease, IBD, 2 and cancer (8,10,14,15).…”

“…Studies with meprin knock-out (KO) mice indicate that meprin ␣ expression in the intestine may be protective, as both ␣KO and ␣␤KO mice developed a more severe dextran sulfate sodium-induced colitis compared with wild-type (WT) or ␤KO mice (15,16). In addition, there is a strong correlation between decreased MEP1A mRNA expression in inflamed mucosa of patients with IBD relative to unaffected tissue from all groups (16).…”