title: Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II.
abstract: Interleukin-6 (IL-6) is an important cytokine participating in multiple biologic activities in immune regulation and inflammation. IL-6 has been associated with cardiovascular remodeling. However, the mechanism of IL-6 in hypertensive cardiac fibrosis is still unclear. Angiotensin II (Ang II) infusion in mice increased IL-6 expression in the heart. IL-6 knockout (IL-6-/-) reduced Ang II-induced cardiac fibrosis: 1) Masson trichrome staining showed that Ang II infusion significantly increased fibrotic areas of the wild-type mouse heart, which was greatly suppressed in IL-6-/- mice and 2) immunohistochemistry staining showed decreased expression of α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and collagen I in IL-6-/- mouse heart. The baseline mRNA expression of IL-6 in cardiac fibroblasts was low and was absent in cardiomyocytes or macrophages; however, co-culture of cardiac fibroblasts with macrophages significantly increased IL-6 production and expression of α-SMA and collagen I in fibroblasts. Moreover, TGF-β1 expression and phosphorylation of TGF-β downstream signal Smad3 was stimulated by co-culture of macrophages with cardiac fibroblasts, while IL-6 neutralizing antibody decreased TGF-β1 expression and Smad3 phosphorylation in co-culture of macrophage and fibroblast. Taken together, our results indicate that macrophages stimulate cardiac fibroblasts to produce IL-6, which leads to TGF-β1 production and Smad3 phosphorylation in cardiac fibroblasts and thus stimulates cardiac fibrosis.
authors.affiliation: Beijing An Zhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Ma
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.forename: Yalei
authors.initials: Y
authors.lastname: Han
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.forename: Yongfen
authors.initials: Y
authors.lastname: Qi
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D003094:Collagen