Influence of Alternatively and Classically Activated Macrophages on Fibrogenic Activities of Human Fibroblasts

Activated macrophages regulate fibrogenesis by providing cytokines and growth factors that modulate the proliferation and collagen synthesis of fibroblasts. However, macrophages can be activated in a classical pathway induced by LPS or IFN-γ and an alternative pathway induced by IL-4 or glucocorticoid. Differently activated macrophages display distinct biological features. To clarify the difference between these two subsets of macrophages in the regulatory mechanisms controlling fibrogenesis, human peripheral blood monocytes were used as the source of macrophages and cocultivation of differently activated macrophages and a fibroblast cell line, WI-38, was performed. Alternatively activated macrophages increased the proliferation index and collagen synthesis of cocultivated WI-38 cells in comparison to untreated monocytes, while classically activated macrophages markedly reduced collagen production of cocultivated WI-38 cells. Additionally, mRNA expression and protein production of TGF-β1, PDGF-AA, and PDGF-BB were elevated in alternatively activated macrophages in parallel to their profibrogenic effects. In contrast, expression and production of TNF-α, as well as MMP-7, were enhanced in classically activated macrophages. These findings suggested that alternatively activated macrophages enhance fibrogenesis of fibroblasts by providing profibrogenic factors, while classically activated macrophages inhibit fibrogenesis of fibroblasts by releasing antifibrogenic or fibrolytic factors.