Fig. 1 Schematic representation showing the inflammatory signal transduction network. The proinflammatory cytokines TNF-a, IL-1ß, and IL-6 activate three general signal transduction pathways exemplified by the activation of the nuclear transcription factors NF-?B, NF-IL-6, and STAT-3. TNF-a interacts with the THF-a receptor (TNFR), setting off a cascade of protein phosphorylation leading to the activation of the NF-?B-inducible kinase (NIK), which in turn activates the I-?B kinase (IKK). IKK phosphorylates the inhibitor protein I-?B, releasing NF-?B (p65/p60 heterodimer) to translocate to the nucleus, and binds its recognition site in the promoter regions of the TNF-a and IL-6 genes. IL-1ß interacts with the IL-1ß receptor (IL-1R) and activates NF-?B and the mitogen activation protein kinase (MAPK) pathway (Ras-Raf-MEK). This activation leads to the phosphorylation of NF-IL-6, which binds to the TNF-a and IL-6 promoter cooperatively with NF-?B. Together, they recruit coactivator proteins and activate TNF-a and IL-6 gene transcription. TNF-a and IL-6 can be secreted from the cell and have secondary autocrine and paracrine effects on nearby cells. IL-6 binds its receptor (IL-6R) to activate the JAK/STAT (Janus activating tyrosine kinase/signal transduction and activator of transcription) pathway. In response to activation of the IL-6R, JAK phosphorylates STAT-3, which allows it to form homodimers, translocate to the nucleus, bind IL-6 responsive elements (IL-6RE) within the NF-IL-6 promoter, and activate NF-IL-6 gene transcription. Newly synthesized NF-IL-6 protein then can provide feedback and activate the late expression of the TNF-a and IL-6 genes by interacting with their promoters.