Curcumin steers THP-1 cells under LPS and mTORC1 challenges toward phenotypically resting, low cytokine-producing macrophages.

The persistent activation of intestinal mechanistic target of rapamycin complex 1 (mTORC1) triggered by mucosal stress has been linked to deregulation of the gut immune response resulting in intestinal inflammation and cell death. The present study investigated the regulatory properties of food-derived mTORC1 modulators, curcumin, and piperine, toward the polarization of stimulated macrophages and the differentiation of monocytes at two mTORC1 activity levels (baseline and elevated). To that end, we created stable human THP-1 monocytes exhibiting normal or constitutively active mTORC1. Curcumin or its combination with piperine, but not piperine alone, suppressed mTORC1 kinase activity, curtailed lipopolysaccharide-mediated inflammatory response of THP-1 macrophages, and repressed macrophage activation by inhibiting signaling pathways involved in M1 (mTORC1) and M2 (mTORC2 and cAMP response element binding protein) polarization. The effects of piperine in the curcumin/piperine combination were modest overall, indicating it was curcumin that modulated differentiating monocytes into acquiring a M0 macrophage phenotype characterized by low inflammatory cytokine output.