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

BMC Gastroenterology

Güralp O Ceyhan²  Mark Hartel³  Helmut Friess³  Markus W Büchler²  Thomas Giese⁴  Frank Bergmann¹  Nathalia A Giese²  Jannik Winckler³  Timo Kehl³  Ihsan Ekin Demir³  Jan G D’Haese³ 

[1] Institute of Pathology, University of Heidelberg, Heidelberg, Germany;Department of General Surgery, University of Heidelberg, Heidelberg, Germany;Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str. 22, Munich, D-81675, Germany;Institute for Immunology, University of Heidelberg, Heidelberg, Germany

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

Others  :  858222
DOI  :  10.1186/1471-230X-13-14

 received in 2012-07-18, accepted in 2013-01-12,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 D'Haese et al.; licensee BioMed Central Ltd.

【 图 表 】

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