Fig. 2.

Inflammatory cytokines intracellular pathways. (1) IL-4 and IL-13 induce arginase I expression via STAT6 activation and arginase I efficiently competes with iNOS for substrate l-arginine, causing a decreased output of NO in astrocytes and microglia. (2) High levels of IL-33 and other pro-inflammatory molecules may activate the NF-κB and MAPKs signaling pathways, which induces numerous pro-inflammatory cytokines, chemokines, and neurotoxic mediators, such as IL-1β, IL-6, IL-8, IFN-γ, TNF-α, CCL2, GMF, NO and ROS in astrocytes and microglia. (3) IL-33 binds to p65 in the nucleus as a transcription factor, blocking the conjugation of p65 to the NF-κB transcription factor. It directly inhibits the nuclear translocation of NF-κB, which inhibits the NF-κB downstream pro-inflammatory signaling pathway and suppresses the inflammatory response. (4) These IL-33-induced inflammatory mediators act on neurons and modulate neuroinflammation, neurodegeneration, apoptosis, and synaptic plasticity, ultimately, cognitive function