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Tissue Inhibitor of metalloproteinase-3 Regulates Inflammation in Human and Mouse Intestine

Tissue Inhibitor of metalloproteinase-3 Regulates Inflammation in Human and Mouse Intestine

Ivan Monteleone, Massimo Federici, Massimiliano Sarra, Eleonora Franzè, Viviana Casagrande, Francesca Zorzi, Michele Cavalera, Angelamaria Rizzo, Renato Lauro, Francesco Pallone, Thomas T MacDonald, Giovanni Monteleone

Gastroenterology. 2012 Nov;143(5):1277-1287.e4.

PMID: 22819866

Abstract:

Background & aims:
Tissue inhibitor of metalloproteinases (TIMP)-3 is an inhibitor of matrix metalloproteinases, which regulates tissue inflammation, damage, and repair. We investigated the role of TIMP-3 in intestinal inflammation in human beings and mice.
Methods:
We used real-time polymerase chain reaction and flow cytometry to measure levels of TIMP-3 in intestine samples from patients with Crohn's disease (CD) and those without (controls). We also analyzed TIMP-3 levels in lamina propria mononuclear cells (LPMCs) collected from biopsy samples of individuals with or without CD (controls) and then stimulated with transforming growth factor (TGF)-β1, as well as in biopsy samples collected from patients with CD and then incubated with a Smad7 anti-sense oligonucleotide (knock down). LPMCs and biopsy samples from patients with CD were cultured with exogenous TIMP-3 and levels of inflammatory cytokines were measured. We evaluated the susceptibility of wild-type, TIMP-3-knockout (TIMP-3-KO), and transgenic (TIMP-3-Tg) mice to induction of colitis with 2, 4, 6-trinitrobenzene-sulfonic-acid (TNBS), and the course of colitis in recombinase-activating gene-1-null mice after transfer of wild-type or TIMP-3-KO T cells.
Results:
Levels of TIMP-3 were reduced in intestine samples from patients with CD compared with controls. Incubation of control LPMCs with TGF-β1 up-regulated TIMP-3; knockdown of Smad7, an inhibitor of TGF-β1, in biopsy samples from patients with CD increased levels of TIMP-3. Exogenous TIMP-3 reduced levels of inflammatory cytokines in CD LPMCs and biopsy samples. TIMP-3-KO mice developed severe colitis after administration of TNBS, whereas TIMP-3-Tg mice were resistant to TNBS-induced colitis. Reconstitution of recombinase-activating gene-1-null mice with T cells from TIMP-3-KO mice increased the severity of colitis, compared with reconstitution with wild-type T cells.
Conclusions:
TIMP-3 is down-regulated in inflamed intestine of patients with CD. Its expression is regulated by TGF-β1, and knock-down of Smad7 in intestinal tissues from patient with CD up-regulates TIMP-3. Loss or reduction of TIMP-3 in mice promotes development of colitis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241312	Tissue Inhibitor of Metalloproteinase-3 human			Price

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