TISSUE INHIBITOR OF METALLOPROTEINASE (TIMP)-3 REDUCES PRO-INFLAMMATORY CYTOKINE PRODUCTION BY ULCERATIVE COLITIS MUCOSA CULTURED EX VIVO

BELL I; AMMOSCATO F; BIANCHERI P; CURCIARELLO R; MACDONALD TT

Manchester

Congreso; BSG2014 Annual Meeting; 2014

British Society of Gastroenterology

Introduction: Interleukin (IL)-1b, IL-6, IL-8 and tumor necrosis factor (TNF)-a, are elevated in the inflamed mucosa of patientswith ulcerative colitis and play a central role in driving the pro-inflammatory immune response in this condition. TNF-a is cleavedfrom the cell surface by TNF-a converting enzyme (TACE), which is inhibited by tissue inhibitor of Metalloproteinase (TIMP)-3. Westudied whether the addition of TIMP-3 to inflamed colonic biopsies from ulcerative colitis patients reduced the release of the proinflammatorycytokines TNF-a, IL-1b, IL-6 and IL-8.Methods: Colonic biopsies were obtained from macroscopically inflamed areas of 4 patients with ulcerative colitis undergoingcolonoscopy for a disease flare. Biopsies were then cultured ex vivo for 24 hours in 300ul of serum free HL-1 medium in the absenceor presence of recombinant human TIMP-3 (100ng/ml). The concentration of TNF-a, IL-1β, IL-6 and IL-8 were measured in culturesupernatants by ELISA.Results: Culture with TIMP-3 significantly reduced TNF-a production by inflamed ulcerative colitis biopsies cultured ex vivo (from1365 ug/ml in the absence of TIMP-3 to 45 ug/ml after TIMP-3 addition). Furthermore, the addition of TIMP-3 significantly reducedIL-1b production by inflamed ulcerative colitis biopsies (from 776 ug/ml to 261 ug/ml). There was a trend in the reduction of IL-6(from 3018 ug/ml to 2702 ug/ml), which did not reach statistic significance, and no significant change in IL-8 production (from30812 to 29114.5ug/ml).Conclusion: TIMP-3 administration not only causes a reduction in TNF-a via TACE inhibition but also IL-1β. This raises thepossibility of its use therapeutically in the treatment of ulcerative colitis.