Browsing by Subject "Interleukin-6"

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Wechselwirkungen zwischen humanen Darmmastzellen und humanen Darmfibroblasten
(2008) Montier, Yves; Bischoff, Stephan C.
Fibroblasts (FB) play a central role in the pathogenesis of fibrosis since they are the major source of extracellular matrix proteins. However, the regulation of extracellular matrix production in fibroblasts, the mechanisms that lead to loss of control of extracellular matrix homeostasis during chronic inflammation and the role of human intestinal mast cells are still not fully understood. Mast cells are key effector cells in allergic reactions but also involved in host defense and tissue remodeling processes such as wound healing, angiogenesis, and fibrogenesis. The group pf Prof. Bischoff has shown previously that human intestinal fibroblasts suppress apoptosis in human intestinal MC independent of the known human mast cell growth factors stem cell factor interleukin-3, interleukin-4, and nerve growth factor.In this work I could show that the effects of fibroblasts on mast cells are mediated by interleukin-6. The molecular crosstalk between human mast cells and human fibroblasts, both isolated and purified from intestinal tissue was analyzed. Mast cells survival in the presence of fibroblasts could be blocked using an anti-interleukin-6 antibody. Mast cells incubated with interleukin-6 survived for up to 3 weeks. Intestinal fibroblasts produced interleukin-6 upon direct stimulation by mast cells in co-culture or by mast cell mediators such as tumor necrosis factor alpha, interleukin-1 beta, tryptase or histamine. Moreover, fibroblasts stimulated by mast cell mediators produce the antifibrotic enzyme matrix metalloproteinase-1. Matrix metalloproteinase-1 should be considered as multifunctional molecule since it participates not only in the turnover of collagen fibrils in the extracellular space but also in the cleavage of a number of non-matrix substrates and cell surface molecules suggesting a role in the regulation of cellular behaviour. Noteworthy, fibroblasts co-cultured with mast cells or treated with matrix metalloproteinase-1 lost confluence. Matrix metalloproteinase-1 expression in fibroblasts triggered by mast cells was dependent on the MEK/ERK cascade as shown by inhibitor experiments. In conclusion, this study show that mast cells mediators stimulate fibroblasts to produce interleukin-6, and, vice versa, fibroblasts derived interleukin-6 supports mast cells survival. Furthermore, mast cell mediators induce expression of matrix metalloproteinase-1 in fibroblasts, a key enzyme in fibrolysis, which in turn leads to lost of confluence of cultured fibroblasts. Taken together the results of my work suggest that mast cells accumulating at sites of fibrosis rather limite than promote fibrogenesis.