TIMP-1 inhibition of occludin degradation in Caco-2 intestinal cells: A potential protective role in necrotizing enterocolitis

Background:Necrotizing enterocolitis (NEC), a common intestinal disease affecting premature infants, is a major cause of morbidity and mortality. Previous reports indicate an upregulation of intestinal matrix metalloproteinases (MMPs) activity that may play key roles on the higher permeability of the intestinal barrier, typical to NEC. Recently, TIMP-1, a natural inhibitor of MMP's, was found to be over expressed in preterm human breast milk (HBM). Previous studies have shown that infants fed with HBM have a significant reduction in the incidence of NEC. The aim of the present study was to investigate the possible role that TIMP-1 may play on the maintenance of tight junctions and therefore the gut barrier integrity.Methods:Timp-1-treated Caco-2 intestinal cells were tested for MMP-2 enzymatic activity and cell junction integrity.Results:TIMP-1 inhibited MMP-2 activity, which induced a significant increase in the expression of occludin but not of claudin-4. TIMP-1 did not affect apoptosis.Conclusion:One of the putative mechanisms associated with HBM protection against NEC is mediated by TIMP-1, which downregulates MMP-2 activity, inhibits the degradation of occluding, and preserves tight junctions and gut barrier integrity.