Osteopontin/Eta-1 upregulated in Crohn's disease regulates the Th1 immune response

Abstract

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.

Osteopontin: Role in immune regulation and stress responses

“…OPN plasma concentrations correlate with the severity of Crohn's disease, consistent with a role for OPN in Th1-mediated immune responses (Sato et al, 2005). OPN is anti-inflammatory in the acute phase but pro-inflammatory in the chronic phase of colitis.…”

T-bet-dependent expression of osteopontin contributes to T cell polarization

“…Dysregulated Opn expression has also been implicated in several autoimmune disorders, including murine experimental autoimmune encephalomyelitis (EAE) (8, 9), multiple sclerosis (10), rheumatoid arthritis (11), and atherosclerosis (12, 13). Dysregulated Opn expression has been correlated with excessive Th1 polarization of CD4 ϩ T cells in these disorders (7,14) opening the possibility that Opn gene expression may directly contribute to Th1͞type 1 CD8 ϩ T cells (Tc1) genetic programming. However, the genetic basis of Opn expression in Th-cell subsets is not well understood.…”

“…Opn expression is also essential for effective Th1-dependent granuloma formation and a positive clinical outcome in patients suffering from mycobacterial infection (6), whereas ectopic Opn expression has been implicated in the granulomatous lesions of Crohn's disease (7). Dysregulated Opn expression has also been implicated in several autoimmune disorders, including murine experimental autoimmune encephalomyelitis (EAE) (8,9), multiple sclerosis (10), rheumatoid arthritis (11), and atherosclerosis (12,13).…”

Osteopontin Biomarker in Inflammatory Bowel Disease, Animal Models and Target for Drug Discovery

“…In CD, Gassler et al reported an elevated OPN expression in plasma cells, but not in epithelial cells [9]. Moreover, Sato et al observed an elevated plasma OPN and significant correlation with disease activity in CD, but not in UC [10].…”

“…Several recent reports have suggested an important role for osteopontin (OPN) in the pathogenesis of IBD as well as its possible use as a biomarker [4][5][6][7][8][9][10]. Masuda et al demonstrated that expression of OPN is significantly elevated in the mucosa of patients with UC [6].…”