Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597354
1. Fibrogenesis
Georg Thieme Verlag KG Stuttgart · New York

Hepatic stellate cells down-regulate pro-apoptotic effector abundance and secretion in mast cells

SK Meurer
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Aachen, Germany
,
M Neß
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Aachen, Germany
,
R Weiskirchen
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Aachen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

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Background: Fibrosis and its resolution depend on hepatic stellate cell (HSC) activation and apoptosis [1]. Mast cells (MCs) are recruited to the liver during fibrosis and they do express potent pro-apoptotic proteins granzyme B (gzmB) and cleaved caspase 3 which are both functionally linked [2, 3].

Methods and Results: Co-culture of HSC and MCs (L138.8A) leads to an increase in gzmB and decrease in cleaved caspase 3 abundance. This modulation in protein quantities is accompanied by reduced STAT5 and p42/p44 activation. In line, the treatment of MC (L138.8A) with TGF-β1 leads to a decrease of cellular activated gzmB and cleaved caspase 3. This coincides with a reduced activation of STAT5 and p42/p44 which is observed in L138.8A and in primary isolated peritoneal mast cells (PMC) [4]. L138.8A which are challenged with IgE and antigen, secrete gzmB and cleaved caspase 3 in an ERK-dependent manner. Secretion of both proteases is reduced in the presence of TGF-β1, an effect which can be reverted by the ALK5 inhibitor SB431542 in case of cleaved caspase 3.

Conclusions: These results suggest that TGF-β1 that is released by activated HSC in co-culture leads to a reduction in STAT5 and ERK activity causing reduced secretion of active cleaved caspase 3.

References:

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[2] Pardo J, Wallich R, Ebnet K, Iden S, Zentgraf H, Martin P, Ekiciler A, Prins A, Müllbacher A, Huber M, Simon MM. Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin. Cell Death Differ 2007;14:1768 – 79.

[3] Zorn CN, Pardo J, Martin P, Kuhny M, Simon MM, Huber M. Secretory lysosomes of mouse mast cells store and exocytose active caspase-3 in a strictly granzyme B dependent manner. Eur J Immunol 2016;43:3209 – 18.

[4] Meurer SK, Neß M, Weiskirchen S, Kim P, Tag CG, Kauffmann M, Huber M, Weiskirchen R. Isolation of mature (peritoneum-derived) mast cells and immature (bone marrow-derived) mast cell precursors from mice. PLoS ONE 2016;11(6):e0158104.