Role of vascular endothelial growth factor in protein loss of Ménétrier's disease.

Vascular endothelial growth factor (VEGF) promotes protein leakage from blood vessels and endothelial cell growth. The expression of transforming growth factor (TGF)-alpha and its receptor is increased in the gastric mucosa of patients with Ménétrier's disease. Since TGF-alpha stimulates the expression of VEGF mRNA in cultured keratinocytes, we hypothesized that VEGF may play an important role in the protein leakage of Ménétrier's disease. Immunohistochemistry was performed using specific antibodies against VEGF and CD31 in gastric tissue specimens from 7 patients with Ménétrier's disease and 10 controls. The effect of recombinant TGF-alpha on VEGF production by cultured lamina propria mononuclear cells (LPMCs) was assessed. VEGF expression was detected for LPMCs and occasional epithelial cells of the gastric mucosa of Ménétrier's patients. VEGF-positive LPMCs were increased in tissues from patients with Ménétrier's disease (P<0.001). Of the LPMCs, T-lymphocytes and macrophages were the major sources of VEGF. CD31-positive blood vessels were increased in Ménétrier's tissue. (P<0.05). Recombinant TGF-alpha induced the production of VEGF in cultured LPMCs (P<0.05). In conclusion, the increased expression of VEGF, as a result of overproduction of TGF-alpha, may play a key role in the pathophysiology of Ménétrier's disease.

Pro-inflammatory signaling by Jun-N-terminal kinase in inflammatory bowel disease.

Since Jun-N-terminal kinase participates in intracellular signaling cascades resulting in inflammatory responses, inhibiting this pathway may represent a new treatment for inflammatory bowel disease including ulcerative colitis and Crohn's disease. However, the functional significance of the activation of this kinase in inflammatory bowel disease remains unclear. We investigated whether Jun-N-terminal kinase activation is increased in inflammatory bowel disease and analyzed the effects of SP600125, which decreases inflammatory cytokine synthesis by inhibiting the phosphorylation of this kinase. Phosphorylation of the kinase was examined in affected human colon using an enzyme-linked immunosorbent assay and immunohistochemistry. The effect of SP600125 on cytokine production was examined in cultures of patients' leukocytes and colonic tissue. Finally, rats received injection of SP600125 (30 mg/kg, s.c.) or vehicle twice daily 2 h before the induction of colitis with dextran sulfate sodium. SP600125 effects were determined observationally and histologically. Colonic tissue contained increased phosphorylated kinase in patients with inflammatory bowel disease with expression localized to the nucleus of epithelial and lamina propria mononuclear cells in lesions. Culturing mononuclear cells or colonic tissue with SP600125 down-regulated inflammatory cytokine production. Prophylactic treatment with SP600125 significantly reduced clinical and pathological scores in dextran sulfate sodium-treated rats. This first demonstration of the pathogenetic role of Jun-N-terminal kinase in the development of intestinal inflammation suggests that inhibiting its phosphorylation could benefit patients with inflammatory bowel disease.

Interleukin-10 in the pathophysiology of inflammatory bowel disease: increased serum concentrations during the recovery phase.

Using a specific enzyme-linked immunosorbent assay, IL-10 concentrations were measured in serum from 62 patients with ulcerative colitis (UC), 43 with Crohn's disease (CD), 25 with other colitides, and 44 normal control subjects. Serum IL-10 concentrations were increased in patients with active UC but not in those with active CD when compared with normal control subjects. A time course study showed that in patients with UC and CD, serum concentrations of IL-6 and C-reactive protein increased during the acute phase and returned to normal as patients go into remission. Notably, serum IL-10 concentrations increased during the phase of disease resolution and declined thereafter regardless of the treatment modality. Gel filtration analysis indicated that IL-10 circulated predominantly as a dimer. In conclusion, this study shows that serum IL-10 is increased during disease recovery in patients with inflammatory bowel disease, and may be a helpful marker in monitoring disease status.