Mast cells inhibit activation and profibrogenic activities of hepatic stellate cells

Background: Mast cells (MC) have been implicated in the process of fibrosis in different organ systems [1]. Their biological effects are either based on an intimate relationship of MC and fibroblasts via soluble mediators [2, 3] or direct cellular interaction [4, 5].

Methods and Results: A direct co-culture of activated hepatic stellate cells (HSC) [6] and a murine MC line (L-138.8A) in the presence/absence of IL-3 and/or TGF-β1 was performed. Proteins of the supernatant, the adherent cells (HSC) and the suspension cells (MC) were analyzed by Western blot. In the presence of MC the expression of collagen IV (supernatant) and connective tissue growth factor (CTGF; supernatant and lysate) was markedly reduced. Furthermore, the expression of activation markers of HSC, e.g. α-SMA, was silenced. The corresponding TGF-β-receptors RII and Endoglin were downregulated which most likely is the basis for the reduced Smad signaling as evidenced by lower Smad2 phosphorylation (HSC).

Conclusions: Direct co-culture of MC and HSC leads to a reduction in TGF-β1-signaling by causing reduced receptor expression and consecutive Smad activation. This leads to a block in HSC activation and matrix gene expression.

References:

[1] Overed-Sayer C, Rapley L, Mustelin T, Clarke DL. Are mast cells instrumental for fibrotic diseases? Front. Pharmacol. 2014;4:1 – 10.

[2] Gaca MDA, Zhou X, Benyon C. Regulation of hepatic stellate cell proliferation and collagen synthesis by proteinase-activated receptors. J. Hepatol. 2002;36:362 – 369.

[3] Dong X, Zhang C, Ma S, Wen H. Mast cell chymase in keloid induces profibrotic response via transforming growth factor-β1/Smad activation in keloid fibroblasts. Int. J. Clin. Exp. Pathol. 2014;7:3596 – 3607.

[4] Gaca MDA, Pickering JA, Arthur MJP, Benyon RC. Human and rat hepatic stellate cells produce stem cell factor: a possible mechanism for mast cell recruitment in liver fibrosis. J. Hepatol. 1999;30:850 – 858.

[5] Wygrecka M, Dahal BK, Kosanovic D, Petersen F, Taborski B, von Gerlach S, Didiasova M, Zakrzewicz D, Preissner KT, Schermuly RT, Markart P. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis. Am. J. Pathol. 2013;182:2094 – 2108.

[6] Meurer SK, Alsamman M, Sahin H, Wasmuth HE, Kisseleva T, Brenner DA, Trautwein C, Weiskirchen R, Scholten D. Overexpression of endoglin modulates TGF-β1-signalling pathways in a novel immortalized mouse hepatic stellate cell line. Plos One 2013;8:e56116.

Corresponding author: Meurer, Steffen K

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