Receptors That Inhibit Macrophage Activation: Mechanisms and Signals of Regulation and Tolerance

Figure 2

Inhibition mechanism of IL-12 production through interaction of TIM-3 and Gal-9. Graphic representation of the TLR4-signaling pathway (black arrows) when activated by LPS (to simplify, not all proteins involved are shown), which induces phosphorylation of diverse nuclear factors, such as NF-κB (p50-p65), AP-1, and STAT1. These nuclear factors induce production of proinflammatory molecules like IL-12. When TIM-3 interacts with Gal-9, phosphorylation of the intracellular portion of TIM-3 is induced and activates the regulatory pathway mediated by this protein. While we do not yet know the precise inhibition mechanism in macrophages, studies have identified a decrease in STAT1 phosphorylation and an increase in STAT3 phosphorylation (red arrows). The result of this change is reduced IL-12 production and increased IL-23 production.