Signal transduction inflammation pathways

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help imderstand its role in signal transduction pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss [28-38]. In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as mahgnant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,... 

Kyriakis JM, Avruch J. 2001. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81 807-869. 

Pro-inflammatory cytokines are important mediators of inflammation and tissue destruction. This section describes two cell-based assays that were used to screen for inhibitors of cytokine production and some of the compounds discovered using these screens. The two screens were important elements of a collaboration between Xenova Ltd and the Suntory Institute of Biomedical Research to find microbial metabolites with potential utility for the treatment of rheumatoid arthritis. Both screens were cell stimulatory assays with similar formats, the principle of which is illustrated in Figure 3. Treatment of cells with a particular stimulus activates a signal transduction pathway, one of the end results of which is production of a cytokine, which is secreted into the assay medium. After a separation step, the cytokine of interest is measured quantitatively in the supernatant by dissociation enhanced lanthanide fluorescence immunoassay (DELFIA) using a europium-labeled tertiary antibody. At the same time, cytotoxic properties of test substances are determined by assessing their effect on proliferation of the separated cells. 

Inhibit production of Thl cytokines, such as TNF-o, IFN-y, IL-2, IL-6, and IL-12. Disrupt formation of the TRAF6-MyD88-IRAK complex responsible for activating crucial signal transduction pathways (p38MAPK, INK, and IKK) involved in inflammation. 

Ali S, Mann DA. 2004. Signal transduction via the NF-kappaB pathway A targeted treatment modality for infection, inflammation and repair. Cell Biochem Funct 22 67-79. 

Superoxide dismutase Inhibition of cell proliferation Inhibition of inflammation Induction of cell-cycle arrest Induction of apoptosis Inhibition of signal transduction pathways Antiangiogenesis... 

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