TNF and inflammatory bowel disease: Figure 2 shows three intracellular signaling pathways that are potentially involved in the pathogenesis of IBD: (1) altered sphingolipid metabolism, whereby the enzyme sphingosine kinase (SK) appears to play a critical role in signaling by TNF-α [9–11], (2) upregulation of immunoproteasome subunits by proinflammatory cytokines, which downstream is connected to activation of the NF-κB signal transduction system [5–8, 33–35], and (3) dual activation of NF-κB and STAT3 signal pathways by cytokines, which results in enhanced IL-17 production by leukocytes [29, 36, 37].