[HTML][HTML] Mesenchymal stem cell-derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL-6-dependent mechanism in the aging …

KA Cieslik, JA Trial, ML Entman - The FASEB Journal, 2015 - ncbi.nlm.nih.gov
The FASEB Journal, 2015ncbi.nlm.nih.gov
Fibrosis in the old mouse heart arises partly as a result of aberrant mesenchymal fibroblast
activation. We have previously shown that endogenous mesenchymal stem cells (MSCs) in
the aged heart are markedly resistant to TGF-β signaling. Fibroblasts originating from these
MSCs retain their TGF-β unresponsiveness and become inflammatory. In current studies, we
found that these inflammatory fibroblasts secreted higher levels of IL-6 (3-fold increase, P<
0.05) when compared with fibroblasts derived from the young hearts. Elevated IL-6 levels in …
Abstract
Fibrosis in the old mouse heart arises partly as a result of aberrant mesenchymal fibroblast activation. We have previously shown that endogenous mesenchymal stem cells (MSCs) in the aged heart are markedly resistant to TGF-β signaling. Fibroblasts originating from these MSCs retain their TGF-β unresponsiveness and become inflammatory. In current studies, we found that these inflammatory fibroblasts secreted higher levels of IL-6 (3-fold increase, P< 0.05) when compared with fibroblasts derived from the young hearts. Elevated IL-6 levels in fibroblasts derived from old hearts arose from up-regulated expression of Ras protein-specific guanine nucleotide releasing factor 1 (RasGrf1), a Ras activator (5-fold, P< 0.01). Knockdown of RasGrf1 by gene silencing or pharmacologic inhibition of farnesyltransferase (FTase) or ERK caused reduction of IL-6 mRNA (more than 65%, P< 0.01) and decreased levels of secreted IL-6 (by 44%, P< 0.01). In vitro, IL-6 markedly increased monocyte chemoattractant protein-1-driven monocyte-to-myeloid fibroblast formation after transendothelial migration (TEM; 3-fold, P< 0.01). In conclusion, abnormal expression of RasGrf1 promoted production of IL-6 by mesenchymal fibroblasts in the old heart. Secreted IL-6 supported conversion of monocyte into myeloid fibroblasts. This process promotes fibrosis and contributes to the diastolic dysfunction in the aging heart.—Cieslik, KA, Trial, J., Entman, ML Mesenchymal stem cell-derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL-6-dependent mechanism in the aging mouse heart.
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