Macrophages (M Phi s) exhibit functional heterogeneity and plasticity in the local microenvironment. Recently, it was reported that M Phi s can be divided into proinflammatory M Phi s (M Phi 1) and anti-inflammatory M Phi s (M Phi 2) based on their polarized functional properties. Here, we report that nicotine, the major ingredient of cigarette smoke, can modulate the characteristics of M Phi 1. Granulocyte-macrophage colony-stimulating factor-driven M Phi 1 with nicotine (Ni-M Phi 1) showed the phenotypic characteristics of M Phi 2. Like M Phi 2, Ni-M Phi 1 exhibited antigen-uptake activities. Ni-M Phi 1 suppressed IL-12, but maintained IL-10 and produced high amounts of MCP-1 upon lipopolysaccharide stimulation compared with M Phi 1. Moreover, we observed strong proliferative responses of T cells to lipopolysaccharide-stimulated M Phi 1, whereas Ni-M Phi 1 reduced T cell proliferation and inhibited IFN-gamma production by T cells. These results suggest that nicotine can change the functional characteristics of M Phi and skew the M Phi 1 phenotype to M Phi 2. We propose that nicotine is a potent regulator that modulates immune responses in microenvironments. (C) 2009 Elsevier Inc. All rights reserved.