Intracellular Pathways

It has become increasingly evident that a combined effect of transcription factors is very important in gene 

The actions of cytokines are very diverse and there is considerable overlap between, their effects. Although the cytokines should be considered as working in a network, an understanding of the potential effect of cytokines is best obtained by considering individual cytokines, particularly those likely to be involved in the asthmatic inflammation. 

IL-1 was one of the first cytokines to be identified. It is secreted predominantly from monocytes and macrophages, but may be produced from several other cell types (Mattoli etal., 1991). IL-1 activity comprises two distinct gene products, IL-la and IL-1, which only have 26% homology, yet appeat to have identical actions 

IL-3 is produced by T lymphocytes, but also by mast cells. In rodents it is important for the development of mast cells and basophils and promotes eosinophil survival (Wasserman, 1990). Antibodies to IL-3 result in a fall in tissue numbers of mast cells in mice. IL-3 has been repotted to protect mast cells from apoptosis, an event likely mediated by the maintenance of intracellular calcium levels (Mekori et al., 1993). Whether IL-3 plays a critical role in mast cell expression in human tissues is not clear and other cytokines including IL-10 and stem cell ffictor c-kit ligand) may also be important. 

IL-5 is of particular interest in the pathophysiology of asthma as it is associated with eosinophilic inflammation (Sanderson, 1992). IL-5 is produced by Tu2-type lymphocytes and there is evidence for increased expression in T lymphocytes in asthmatic airways (Hamid etal., 1991). Endobronchial allergen challenge results in IL-5 mRNA expression in eosinophils in BAL (Broide et al., 1992b) and an increase in IL-5 concentration (Sedgewick et al., 1991 Ohnishi et al., 1993a). Elevated IL-5 concentrations have also been reported in BAL fluid from 

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Retinoids. Figure 1 Intracellular pathways and molecular action of retinoids. 

Number of papers to date have shown that the CXCR4 receptors expressed in both neuronal and glial cells are functional and coupled to multiple intracellular pathways (Lazarini et al. 2003). The CXCR4 through pertussis toxin (PTX)- sensitive G proteins is coupled to at least two distinct signaling pathways (1) the first pathway, involving the activation of phosphatidylinositol- 3 (PI-3) kinase and extracellular signal... 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

Intracellular pathways after escape from the endolysosomal system into the cytosol are less clear. Obvious bottlenecks include, in the case of gene transfer (pDNA delivery), cytosolic transport to the perinuclear area, nuclear uptake, and nuclear presentation of the pDNA to the transcriptional machinery in bioactive form. In the case of siRNA (or mRNA and some other nucleic acids such as oligonucleotides), cytosolic accessibility for the required function is essential. Besides cytosolic transport [176, 177] and the nuclear import of large nucleic acid molecules [178-180], incorporation of functional nuclear import peptide domains has been evaluated [181-186]. Another bottleneck, nucleic acid unpackaging [187], i.e., partial or complete dissociation from the polymeric carrier, which is required for biological accessibility of the delivered nucleic acid, will be discussed in Sect. 3.3. 

Second messengers relay the primary signal. The distinction between second messengers and normal transducers is that second messengers are small molecules. Extracellular signals of various kinds can activate intracellular pathways that cause an increase in the concentration of a small molecule messenger. All of these pathways involve G-protein coupled receptors. There are two second messengers that you need to know about cyclic nucleotides and calcium. 

FIGURE 1 8-3 Intracellular pathway of bioactive peptide biosynthesis, processing and storage. Neuropeptide precursors are synthesized on ribosomes at the endoplasmic reticulum and processed through the Golgi. Axonal transport of the large dense-core vesicle to the synaptic site of release precedes the actual secretion. 

Both NMDA and AMPA/kainate receptors contribute to excitotoxic neuronal degeneration of neurons and glia 563 Excitotoxicity leads to increased Ca2+ and Zn2+, which can activate cytotoxic intracellular pathways 564... 

Polygenic analyses of the MTX pathway genes have also been perfonned. This is particularly relevant in the case of MTX as the drug exerts its effects by influencing several different genes in the intracellular pathways. AIC AR transfonnylase (ATIC) converts AlCAR to 10-formyl AlCAR and is directly inhibited by MTX see Fig. 14.1). This leads to accumulation of AlCAR and adenosine, a purine with antiinflammatory properties. Adenosine may be an important mediator of the antiinflammatory effects of MTX (11). 

The calcium current through the NMDA receptor related ion channel becomes the signal that co-incident events have been detected (Lynch et al., 1983) and activates further intracellular pathways. Several potential transduction mechanisms could lead to the long-term expression of LTP including the protease cal-... 

Morikawa H, Khodakhah K, Williams JT (2003) Two intracellular pathways mediate metabotropic glutamate receptor-induced Ca2-I- mobilization in dopamine neurons. J Neurosci 23 149-157... 

LEG evidence for cis-/tr r-activa-tion of selected intracellular pathways... 

InCeP intracellular pathway based on mKIAA protein-protein interactions DNA Res 12, 379-387. 

A target cell that receives a signal within the framework of intercellular communication transmits the signal in intracellular pathways. These signaling pathways are characterized by the following parameters ... 

Arrestin then interacts with clathrin and clathrin adaptor AP2, leading to endocytosis of the receptor. In addition to blunting responses requiring the presence of the receptor on the cell surface, these regulatory processes may also contribute to novel mechanisms of receptor signaling via intracellular pathways. 

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