A set of cell surface receptors (Figure 4-2A) act through cell signal transduction pathways to activate NFκB. This links the message of “stress” to the cell nucleus, where inflammatory mediators are in turn generated (Figure 4-2, row B). One of the more important triggers of NFκB-induced inflammatory pathway activators include the tumor necrosis factor alpha (TNF-α). TNF-α is secreted very early in the inflammatory process, usually from immune system cells in response to infections. TNF-α, originally discovered as a serum factor related to cancer, is also secreted in high amounts from the connective tissue surrounding malignancies, and from adipocytes. It has several subtypes of specific cell surface receptors that act to transmit the message of inflammation, which in turn activates NFκB and leads to the expression of a host of inflammatory mediators as described below. Interleukin-1 (IL-1) is most often secreted in response to infections and injury, and activates and amplifies inflammatory signaling through its own cell surface receptor. In addition, IL-1 has recently been identified as a major cytokine that is secreted from senescent cells, providing support that may play an important role in late life activation of inflammatory pathways.7 In addition to these early inflammatory cytokine signals, the bacterial surface antigen lipopolysaccharide (LPS) and some viral particles bind to a family of cell surface toll-like receptors (TLR), which in turn set off a separate signal transduction pathway that in turn amplifies NFκB-related inflammatory signaling. This pathway to inflammatory activation is certainly crucial for the protection of the organism against acute infections, and likely also helps in organized defense against chronic infections. Recent evidence suggests that thrombin, a clotting component, may also activate inflammatory pathways through its own receptor. This provides a link between injury and inflammation. Finally, and potentially very important for aging-related activation of inflammatory systems, the free radicals superoxide and hydrogen peroxide activate inflammatory pathways via signal transduction pathways that facilitate NFκB-mediated inflammatory gene production (Figure 4-2, row A). In sum, all of these specific activating molecules, cell surface receptors, and signal transduction pathways, no matter what the ultimate triggering mechanisms is, transmit the message of stress to the nucleus of the cell, where NFκB-related activity induces the expression of inflammatory mediators that act to either amplify the inflammatory message or exert negative feedback that brakes inflammatory signaling as described below (Figure 4-2).