Suppressive effects of cyclosporine A on neutrophils and T cells may be related to therapeutic benefits in patients with steroid-resistant ulcerative colitis.

An intravenous infusion of cyclosporine A (CsA) shows clinical benefits in patients with steroid-resistant ulcerative colitis (UC). To clarify its mechanisms, we investigated the ability of CsA to inhibit the functions of neutrophils and T cells. The cytotoxic activity by mucosal T cells was analyzed by anti-CD3-triggered cytotoxicity after lamina propria mononuclear cells were cultured with recombinant interleukin (IL)-2. The chemotactic response, the generation of superoxide, and the production of chemokines, IL-8, and macrophage inflammatory protein-1alpha by neutrophils were examined using a multiple-well chamber assay, a chemiluminescence method, and an enzyme-linked immunosorbent assay (ELISA), respectively. Mucosal chemokine activity was determined by an ELISA using the organ culture supernatant of mucosal biopsy tissues. Pretreatment with CsA caused consistent inhibitions of cytotoxic activity by mucosal T cells and chemotactic migration, superoxide generation, and chemokine production by neutrophils mostly in a dose-dependent manner. In patients who received an intravenous infusion of CsA, mucosal chemokine activity decreased after therapy in parallel with decreases in the numbers of neutrophils and mononuclear cells in the biopsy tissues. These results suggest that suppressive effects of CsA on neutrophils and T cells may be related to therapeutic benefits in patients with steroid-resistant UC.

Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitis.

BACKGROUND: Little information is available on the relative contribution of peptide growth factors and leukocyte-derived proteinases to the repair processes in inflammatory bowel disease (IBD). We investigated their possible roles in epithelial cell restitution and proliferation in patients with IBD. METHODS: The expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-beta (TGF-beta), and neutrophil elastase (NE) was examined in colonic mucosal tissues. The effects of organ culture supernatants of mucosal tissues on epithelial cell restitution and proliferation were analyzed in vitro using an intestinal cell line, IEC-6 cells. RESULTS: Most organ cultures detected the presence of measurable levels of HGF, with a relative paucity of KGF and TGF-beta activity. Greater levels of HGF were obtained in the mucosa involved with IBD, especially in patients with ulcerative colitis (UC). The mucosa involved with UC also showed higher amounts of NE. The supernatants from the mucosa involved with UC possessed a prominent stimulatory effect on the restitution of IEC-6 cells. By contrast, significant suppression beyond baseline levels was observed for the proliferation of IEC-6 cells when they were incubated with recombinant HGF plus the supernatants from the mucosa involved with UC. This suppression was diminished considerably by preincubation of the supernatants with the anti-NE antibody. CONCLUSIONS: HGF produced in the intestinal mucosa may be an important stimulator acting on epithelial cell restitution in patients with IBD. However, NE released in situ may impair mucosal repair through inhibiting epithelial cell proliferation in patients with UC.