| First Author | Cieslik KA | Year | 2015 |
| Journal | FASEB J | Volume | 29 |
| Issue | 8 | Pages | 3160-70 |
| PubMed ID | 25888601 | Mgi Jnum | J:225456 |
| Mgi Id | MGI:5693333 | Doi | 10.1096/fj.14-268136 |
| Citation | Cieslik KA, et al. (2015) Mesenchymal stem cell-derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL-6-dependent mechanism in the aging mouse heart. FASEB J 29(8):3160-70 |
| abstractText | 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-beta signaling. Fibroblasts originating from these MSCs retain their TGF-beta 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. |
