Osteopontin, a Protein with Cytokine‐like Properties, is Associated with Inflammation in Crohn's Disease

Abstract

In Crohn's disease (CD) mucosal T‐cells produce increased interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) levels and TNF‐α antibody treatment [Infliximab (Ifx)] is effective. Osteopontin (OPN), a glycoprotein stimulating activated T‐lymphocytes, may be involved in the disturbed immune‐regulation but also in normal immune‐homeostasis and mucosal repair, since it is expressed in many tissues and present in human milk. This study investigates plasma‐OPN levels in CD patients during Ifx treatment and the in vitro effect of OPN on intestinal T cells. Thirty‐seven CD patients received three Ifx doses at week 0, 2 and 6. Blood samples, colonic biopsies and clinical scores were obtained before treatment and at week 8, 26 and 52. In‐vivo activated T‐cell cultures were established from colonic biopsies in the presence of interleukin (IL)‐2 and IL‐4. The in vitro effect of OPN stimulation on T‐cell IFN‐γ, TNF‐α, and IL‐10 production was measured. Plasma‐OPN was increased in active CD (increased CRP‐level) compared with quiescent disease (P = 0.02) and declined after three Ifx doses (P = 0.04). It was inversely correlated with in vitro T‐cell IL‐10 production. OPN increased CD69 and CD25 expression and enhanced T‐cell IFN‐γ and TNF‐α production in a dose‐dependent fashion with higher levels in CD than in healthy controls (HC), but induced a concomitant higher IL‐10 production in HC than CD. In conclusion, plasma‐OPN levels are related to CD inflammation. In vitro, OPN‐stimulated IL‐10 production increases less in T‐cell cultures from CD patients than from HC, indicating that IL‐10 deficiency may be involved in the defect immune‐regulation in CD, even after OPN stimulation.

Osteopontin: Role in immune regulation and stress responses

“…Moreover, soluble OPN may modulate the differentiation and proliferation of CD4 + and CD8 + T cells (Higuchi et al, 2004). Shinohara et al (2005) Recent evidence indicates that plasma OPN levels increase in active Crohn's disease compared with quiescent disease and decline after treatment with the anti-TNF-α monoclonal antibody infliximab (Agnholt et al, 2007). Furthermore, OPN regulates cell-mediated immunity by promoting T cell proliferation and migration as demonstrated in transgenic mice over-expressing OPN; these mice also exhibited an increase in the percentage of CD4 + T cells in lymph nodes (Higuchi et al, 2004).…”

Plasma Osteopontin Predicts Inflammatory Bowel Disease Activities

“…10 With respect to IBD, Gassler et al first demonstrated increased OPN expression in the terminal ilea of patients with CD. 11 Significant correlations between plasma OPN levels and the disease activities of CD 12,13 and UC 14 have been reported. In the context of UC, we reported a 23.4-fold increase in OPN mRNA expression compared with normal control colon tissues using gene-chip analysis.…”

Osteopontin Mediates Citrobacter rodentium-Induced Colonic Epithelial Cell Hyperplasia and Attaching-Effacing Lesions

“…11,27 In these patients, OPN is produced by gut epithelia, IgG-producing plasma cells, and macrophages. 28,29 Increased OPN expression in areas of active inflammation suggests that OPN is involved in stimulating cytokine production that contributes to a T H 1-predominant adaptive immune response, as is observed in Crohn's disease. 21 Since OPN is also associated with a decrease in the production of the anti-inflammatory cytokine IL-10 by T cells from patients with Crohn's disease, 28 OPN-mediated defects in immune-regulation may further contribute to the development of inflammation.…”