Interleukin 1-stimulated intracellular signaling

We have developed a preliminary kinetic model of the interleukin 1 (IL-1)-stimulated intracellular signaling pathway in epidermal keratinocytes as an initial effort toward the pharmacodynamic modeling of the skin. On exposure to external stimuli, such as chemical irritants, the skin secretes various cytokines and chemo-kines and evokes a cascade of events in the subcutaneous tissue. Therefore, the pharmacodynamic process of the skin primarily involves the responses of the skin cells to these endogenous proteins. Among them, one of central importance is IL-1, a proinflammatory cytokine that mediates the host defense activities of the skin. The model captures the series of biochemical events initiated from IL-1 a binding to IL-1 receptor (type I) on the cell surface that activates the transcriptional factor nuclear factor (NFk-B) and leads to production of a responsive protein, IL-6, as illustrated in Figure 6.6. 

Further evidence for the importance of imine formation for T cell function was derived from the discovery that tucaresol and other small molecules with an aromatic aldehyde moiety capable of forming Schiff bases, produces a signal to CD4+ T helper (Th) cells [62]. Tucaresol reacts in vitro with free CD4+ T cell surface amines from receptors like CD2 within seconds to cause a co-stimulatory signal to produce a Thl response with the release of interferon y (IFN-y) and a 5- to 10-fold increase of interleukin 2 (IL-2). Such a Thl response is believed to be important for intracellular pathogens such as viruses, mycobacteria, protozoa and tumors. Studies in vivo show that low concentrations of tucaresol enhance not only CD4+ Th cells in response to antigens but also CD 8+ CTL and that this response has a beneficial effect in antiviral and antitumor therapy in animal models. Mechanistically, formation of Schiff bases with tucaresol has been shown to greatly affect intracellular potassium and sodium ion concentrations by the co-stimulation of mitogen-activated protein kinase (MAP kinase) and thus activation of ion channels in T cells [62,102]. Some of these mechanistic features are depicted in Fig. 19. 

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