Background and aims: The pathogenesis of Crohn's disease (CD), a chronic inflammatory bowel disease characterised by a Th1 immune response, remains unclear. Osteopontin (OPN) is a phosphoprotein known as an adhesive bone matrix protein. Recent studies have shown that OPN plays an important role in lymphocyte migration, granuloma formation, and interleukin 12 (IL-12) production. The present study investigated expression and the pathophysiological role of OPN in CD. Methods: Plasma OPN concentration was measured by enzyme linked immunosorbent assay. Expression of OPN in human intestinal mucosa was determined using reverse transcription-polymerase chain reaction and western blot, and localisation of OPN was examined by immunohistochemistry. Expression of integrin b 3 , an OPN receptor, on lamina propria mononuclear cells (LPMC) was assessed by flow cytometry. Functional activation of OPN in LPMC was investigated by measuring the production of cytokines. Results: Plasma OPN concentration was significantly higher in patients with CD compared with normal controls or patients with ulcerative colitis (UC). OPN was upregulated in intestinal mucosa from UC and CD patients. OPN producing cells were epithelial or IgG producing plasma cells, or partial macrophages. OPN was detected in areas surrounding granuloma from mucosa in CD. Integrin b 3 expressing macrophages infiltrated inflamed mucosa in UC and CD; in contrast, there was no expression of integrin b 3 on intestinal macrophages in normal mucosa. OPN induced production of IL-12 from LPMC in CD but not in normal controls or UC. Conclusions: Increased OPN expression facilitates cytokine production and is closely involved in the Th1 immune response associated with CD.

Splenic macrophages and alveolar macrophages may be related to excessive production of TNF-alpha in acute alcoholics with endotoxemia.

Background: It is suggested that endotoxin and proinflammatory cytokines play an important role in the development and progression of alcoholic liver disease. Recently, a prostaglandin receptor subtype EP4 agonist with cytoprotective effect has been developed. We examined the efficacy of an EP4 agonist ONO-AE1-437 on tumor necrosis factor-␣ (TNF-␣) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol-loaded rats.Methods: Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from control and acute ethanol-loaded rats (5 mg/g body weight of ethanol, intraperitoneally). After the preculture in the medium that containing 0, 0.1, 1, 10, or 100 nmol/liter of ONO-AE1-437, TNF-␣ secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr.Results: The amount of TNF-␣ secreted from alveolar macrophages was largest in both the control and the acute ethanol-loaded rats. Acute ethanol load enhances TNF-␣ secretion of splenic macrophages. The addition of ONO-AE1-437 significantly inhibited TNF-␣ secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol-loaded rats. Alveolar macrophages were less affected.Conclusions: An EP4 agonist ONO-AE1-437 suppresses excess TNF-␣ secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.

An EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.

No abstract