Abstract
Macrophage infiltrations (inflammation) are associated with prostate disorders such as prostatitis, prostatic hyperplasia and prostate cancer. All prostate disorders have elevated cell proliferation, and are initiated from normal prostate epithelial cells. To date, the mechanism of how macrophages regulate normal prostate epithelial cell proliferation remains largely unknown. Using a 3D co-culture system, we here show that Raw 264.7 macrophages increased cell proliferation of normal prostate epithelial PZ-HPV-7 cells. In addition, these Raw 264.7 macrophages expressed higher levels of Ym1 and CD206. We further identify macrophage-secreted cytokines including CCL3, IL-1ra, osteopontin, M-CSF1 and GDNF as mediators for potentiating PZ-HPV-7 cell proliferation in 3D. All these cytokines differentially activated ERK and Akt. Blockade of both kinases through their inhibitors hindered macrophage-induced cell proliferation of PZ-HPV-7 cells. Hence, our data provide mechanistic insight of how inflammation may contribute to development of prostatic diseases at a very early stage through augment of cell proliferation of normal prostate epithelial cells.
Highlights
We, show that macrophage-secreted cytokines are mediators to increase cell proliferation of normal prostate epithelial cells in a 3D cell culture system
To decipher the effect of macrophage-mediated process on cell proliferation of normal prostate epithelial cells, we co-cultured Raw 264.7 macrophages with immortalized normal prostate PZ-HPV-7 epithelial cells on matrigel in a three dimensional setting. These two types of cells were seeded in separated compartments of a co-cultivation system, which only allows cells to share soluble substances released in the media instead of physical contacts
Raw 264.7-conditioned media had a better effect on PZ-HPV-7 cell proliferation as compared to co-cultivation of Raw 264.7 macrophages
Summary
Show that macrophage-secreted cytokines are mediators to increase cell proliferation of normal prostate epithelial cells in a 3D cell culture system. These macrophage cytokines activate ERK and Akt, and inhibition of both protein kinases abolish macrophage-medicated cell proliferation. Scale bar: 20 μm. (E) Cell proliferation index of PZ-HPV-7 cells that were cultured in 3D with control media or Raw 264.7-conditioned media was quantified. *p < 0.05
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