Z Gastroenterol 2015; 53 - A1_31
DOI: 10.1055/s-0035-1567961

Regulation and profibrogenic effects of TGF-β1 signaling in mast cells, a cell type contributing to the outcome of hepatic injury

M Neß 1, JM Bangen 3, M Huber 2, C Liedtke 3, R Weiskirchen 1, SK Meurer 1
  • 1RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chenistry, Aachen, Germany
  • 2RWTH University Hospital Aachen, Institute of Biochemistry and Molecular Immunology, Aachen, Germany
  • 3RWTH University Hospital Aachen, Department of Internal Medicine III, Aachen, Germany

Background: In the setting of mastocytosis, mast cells have been shown to promote renal and lung fibrosis, whereas their effect in the liver is under debate [1 – 4]. Mast cell effects are based on the secretion of mitogenic and profibrotic, e.g. TGF-β1, cytokines – leading to activation and proliferation of fibroblasts [5] – and proteases – causing a direct or indirect modulation of extracellular matrix homeostasis [6]. Besides these paracrine effects, mast cells are able to process TGF-β1 signals on their own but the exact mechanisms and responses are less well characterized.

Material and Methods: The impact of profibrogenic TGF-β signaling on mast cell biology was analyzed in primary bone marrow-derived murine mast cells (BMMC) and immortalized murine and human mast cell lines by qRT-PCR, western blot and immunocytochemistry.

Results: BMMC and commonly used mast cell lines, e.g. human HMC1.1 and murine L-138.8A express the type I (ALK5) and type II TGF-β-receptors. Although ALK1 is only expressed in HMC1.1, Smad2/3 and Smad1/5 activation is seen in all mast cells. In line, the inhibitory/apoptotic effect of TGF-β1 on mast cell proliferation is blocked by the ALK5 inhibitor SB431542, showing that ALK5/Smad axis is critical for TGF-β1 signaling. On the molecular level TGF-β1 reduces the mRNA expression of cyclinE/A and c-myc in BMMC. In the presence of IL-3 the inhibitory effect of TGF-β1 on proliferation is reduced as is phosphorylation of Smads. Nevertheless, cross talk of TGF-β1 is also seen for the activation of STAT5, src and pp42/44. Finally, endoglin, i.e. a TGF-β1-co-receptor, is expressed only in BMMC and sparsely in L-138.8A but not in HMC1.1. Re-expression of endoglin in HMC1.1 modulates the signal transduction of IL-3 and TGF-β1.

Conclusions: These results demonstrate that i) mast cells possess a versatile network to process TGF-β1 signals, ii) TGF-β1 impacts proliferation and differentiation of mast cells, iii) TGF-β1 affects several aspects of IL-3 signaling iv) these effects are modulated by endoglin, a modulatory TGF-β receptor expressed in primary BMMC. These data suggest that targeting TGF-β signaling may provide promising benefits in alleviating inflammatory or fibrotic effects of mast cells in liver injury.

References cited:

[1] Farrell DJ et al. Hepatology 1995;22:1175 – 81.

[2] Armbrust T et al. J. Hepatol. 1997;26:1042 – 54.

[3] Okazaki T et al. Lab. Invest. 1998;78:1431 – 8.

[4] Sugihara A et al. J. Hepatol. 1999;30:859 – 67.

[5] Evans RA et al. Exp. Cell Res. 2003;282:90 – 100.

[6] Dong X et al. J. Clin. Exp. Pathol. 2014;7:3596 – 607.

Corresponding author: Meurer, Steffen Klaus

E-Mail: smeurer@ukaachen.de