Schematic examples of cytokine signal modulation. (a) Priming: upon exposure to suboptimal levels of type I interferon or IL-6, no signal is generated; but if later the cell (macrophage) sees suboptimal levels of IFNγ, then gene transcription initiates and a signal is generated [67, 68]. IDO, indoleamine-2,3-dioxygenase; IFNAR, interferon alpha receptor IL-6Ra, IL-6 receptor alpha; IRF1, interferon regulatory factor 1; STAT, signal transducer and activator of transcription. (b) Uncoupling of signaling: monocytes chemotactic protein-1 (MCP-1)/CCL2 signal upon CCR2 binding. In the presence of IL-10, binding of MCP-1/CCL2 to CCR2 is preserved but signal is abolished . IL-10R, IL-10 receptor. (c) Reprogramming of signaling: in macrophages, Toll-like receptor (TLR) 2 activation induces TNF, production of which is reduced by simultaneously induced homeostatic IL-10 (negative feedback). If the cell has been primed with type I interferon, however, then IL-10 fails to negatively regulate TLR signaling. In turn, IL-10 becomes a proinflammatory cytokine favoring the production of TNF and other cytokines. The signaling cascade induced by IL-10 shifts form anti-inflammatory STAT 3 to proinflammatory STAT 1 . Figures in circles indicate sequences of events. AP-1, activator protein 1.