Mesenchymal stromal cells regulate THP-1-differentiated macrophage cytokine production by activating Akt/mammalian target of rapamycin complex 1 pathway.

Abstract

The Akt/mammalian target of rapamycin (mTOR) pathway in macrophages converges inflammatory and metabolic signals from multiple receptors to regulate a cell's survival, metabolism and activation. Although mesenchymal stromal cells (MSCs) are well known to modulate macrophage activation, the effects of MSCs on the Akt/mTOR pathway in macrophages have not been elucidated. We herein investigated whether MSCs affect the Akt/mTOR complex 1 (mTORC1) pathway to regulate macrophage polarization. Results showed that human bone marrow-derived MSCs induced activation of Akt and its downstream mTORC1 signaling in THP-1-differentiated macrophages in a p62/sequestosome 1-independent manner. Inhibition of Akt or mTORC1 attenuated the effects of MSCs on the suppression of tumor necrosis factor-α and interleukin-12 production and the promotion of interleukin-10 and tumor growth factor-β1 in macrophages stimulated by lipopolysaccharide/ATP. Conversely, activation of Akt or mTORC1 reproduced and potentiated MSC effects on macrophage cytokine production. MSCs with cyclooxygenase-2 knockdown, however, failed to activate the Akt/mTORC1 signaling in macrophages and were less effective in the modulation of macrophage cytokine production than control MSCs. These data demonstrate that MSCs control THP-1-differentiated macrophage activation at least partly through upregulation of the Akt/mTORC1 signaling in a cyclooxygenase-2-dependent manner.