TNFa signaling, regulation

The stress or growth pathways modulated by vanadium involve specialized effectors and often can be activated by excess ROS. Cytokines, small proteins that effect communication between cells or cell behavior, can be involved in the cellular stress response. Tumor necrosis factor a (TNFa) is a cytokine stress signal that binds to a membrane receptor (tumor necrosis factor receptor, or TNFR). This interaction stimulates kinase activity that leads to cell injury and inflammation and also to the activation of caspases, a family of cysteine-dependent aspartate-directed proteases that are involved in apoptosis. The mitogen-activated protein (MAP) kinase cascade regulates both mitosis and apoptosis signaling pathways. 

Cytokine Production/Cellular Activation TNFa and IFNy mediate the induction of other cytokines (IL-1 and IL-6) and the activation of phagocytes. It has been suggested that particle-induced expression of MIP-2 and cytokine-induced neutrophil chemoattractant CKs in the rat lung are mediated at least in part by production of TNFa. TNF is involved in control of monocyte-mediated regulation of cytokine production by T cells. Preincubation of monocytes with rTNF enhanced their ability to induce IFNy production, and TNF synthesis inhibitors decreased this induction. However, Th2 cells are stimulated in the relative absence of monocyte co-stimulatory signal(s), probably IL-6. Concerning pain responsivity, TNFa produces dose-dependent hyperalgesia mediated via the induced release of IL-lp. ... 

Another approach is the inhibition of the TNF-converting enzyme (TACE), which converts proTNF into its mature, proinflammatory form. Also, numerous inhibitors of P38 and Erk-MAP kinases have been synthesized and some have reached the clinical trial stage. MAP-p38 kinase occupies a central role in the signaling network responsible for the up-regulation of proinflammatory cytokines like interleukin 1 and TNFa. The pathway of Erk-MAP kinase is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. ... 

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