Open Access Research article

The impact of MFG-E8 in chronic pancreatitis: potential for future immunotherapy?

Jan G D’Haese1, Ihsan Ekin Demir1, Timo Kehl1, Jannik Winckler1, Nathalia A Giese2, Frank Bergmann3, Thomas Giese4, Markus W Büchler2, Helmut Friess1, Mark Hartel1 and Güralp O Ceyhan12*

Author affiliations

1 Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str. 22, Munich, D-81675, Germany

2 Department of General Surgery, University of Heidelberg, Heidelberg, Germany

3 Institute of Pathology, University of Heidelberg, Heidelberg, Germany

4 Institute for Immunology, University of Heidelberg, Heidelberg, Germany

For all author emails, please log on.

Citation and License

BMC Gastroenterology 2013, 13:14  doi:10.1186/1471-230X-13-14

Published: 16 January 2013

Abstract

Background

The glycoprotein MFG-E8 mediates phagocytic clearance of apoptotic cells and influences the pathogenesis and progression of inflammatory diseases. MFG-E8 was shown to attenuate the progression of inflammation and to improve survival in septic rats. Accumulating evidence suggests an immunomodulatory link between MFG-E8 and the pro-inflammatory chemokine fractalkine, which may determine the severity of pain, fibrosis, and inflammation in chronic pancreatitis (CP).

Methods

The expression and localization of MFG-E8 was investigated in CP (n = 62), and normal pancreas (NP; n = 34) by QRT-PCR, Western-blot and immunohistochemistry analyses. Results were correlated with mRNA expression of fractalkine, CX3CR1, and with the presence and degree of pain and fibrosis. Human pancreatic stellate cells (hPSCs) were isolated from CP tissues and evaluated for MFG-E8 mRNA expression after fractalkine stimulation.

Results

MFG-E8-mRNA was significantly overexpressed in CP and isolated hPSCs when compared to NP. Western-blot and immunohistochemistry analysis confirmed accumulation of MFG-E8 in CP, with noticeably increased MFG-E8 immunoreactivity in tubular complexes. MFG-E8 expression correlated significantly with fractalkine expression, severe fibrosis, and the presence of pain in CP patients. Stimulation of hPSCs with fractalkine led to a significant increase in MFG-E8 expression.

Conclusions

In the present study, we demonstrated for the first time that MFG-E8 is significantly up-regulated in CP patients and together with fractalkine correlated noticeably with severe fibrosis and the presence of pain. hPSCs overexpress MFG-E8 upon fractalkine stimulation in vitro, which underlines the suggested immunmodulatory link in CP and may be a key mechanism in CP fibrogenesis and pain generation. Taken together, these novel findings suggest that MFG-E8 blockade may be a promising tool for future immunotherapy in CP to attenuate both fibrosis and pain sensation.

Keywords:
MFG-E8; Chronic pancreatitis; Fractalkine; Fibrosis; Stellate cells; Pain