Cytokines actions

Cytokines all function using a group of transmembrane receptors embedded in the plasma membranes of target cells. The receptors have no tyrosine kinase activity but associate with and activate kinases known as Janus kinases (JAKs). These kinases phosphory-late tyrosine side chains in their receptors, and the phosphorylated receptors activate transcription factors of the STAT (signal transducer-activators of transcription) group.186-195 The specificity of cytokine action results from a combination of receptor recognition and recognition of the various STAT molecules by different JAKs.111 Cytokines have a variety of structures. Many are helix bundles or have (3 sheet structures (Fig. 30-6). 

Compounds That Affect Signal Transduction of Cytokine Action or Production... 

Y7. Young, P. R., Pharmacological modulation of cytokine action and production through signaling pathways. Cytokine Growth Factor Rev. 9, 239-257 (1998). 

Mitochondrial oxidative stress and mitochondrial GSH defense affects transcription factor activation. Oxidant stress in mitochondria not only can promote the loss of mitochondrial GSH and mitochondrial functions, but also can promote extramito-chondrial activation of NF-kB and therefore may affect nuclear gene expression. Mitochondria are targets of cytokines leading to the overproduction of reactive oxygen species induced by ceramide, a lipid intermediate of cytokine action and closely associated with apoptosis. Chronic ethanol intake depletes liver mitochondrial glutathione due to an ethanol-induced defect in the transport of GSH from cytosol into the mitochondrial matirix. This sensitizes liver cells to the prooxidant effects of cytokines and prooxidants generated by the oxidative metabolism of ethanol. 

As mentioned above (Section 34.3.4.2) there is growing evidence supporting the hypothesis that schizophrenia is caused by a combination of genetic or epigenetic factors that affect limbic brain structures in the last trimester of development and stress-induced envkonmental influences during the final maturation of these structures late in human adolescence. This two hit idea has led to research directed at two potential targets for cytokine action the effects of cytokines on the... 

Endothelial cells are strategically located at the interface between circulating blood cells and tissues, and are an important source and target of cytokine action (Pober and Cotran, 1990). Cytokines such as IL-1 and TNFa enhance the adherence of white blood cells or modify endothelial jermeability. Endothelial cells also express intercellular adhesion molecules-1 and -2 (ICAM-1, and -2) which are members of the immunoglobulin supergene femUy. Expression of ICAM-1 is increased by exposure of endothelial cells to the cytokines IL-1 and TNFa (Mantovani and Dejana, 1989). These cytokines... 

Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines Actions and mechanisms of action. Physiol Rev 1999 79 1-79. 

Cytokines in most cases modulate tumor-specific inhibition dependent on direct lytic activity of cytotoxic CDS T cells or on polarization of CD4 T cells. But tumor eradication also depends on noncytotoxic CD4 and CDS lymphocytes releasing high amounts of proinflammatory cytokines that recruit distinct effector leukocytes at the tumor site. This series of events emphasizes the cytokine action in the tumor site upon several distinct cell types and immunoinflammatory mechanisms. However eradication of established tumors involves distinct mechanisms, each endowed with a different curative potential and not only cytokines. ... 

In response to cytokine action there is an increase in metabolic rate, leading to an increased rate of oxidation of amino acids as metabolic fuel, so reducing rhe amount available for protein synthesis. 

A variety of plasma proteins synthesized in increased amount in response to cytokine action (the so-called acute-phase proteins) are richer in two amino acids, cysteine and threonine, than most tissue proteins. This leads to depletion of tissue pools of these two amino acids, again leaving an unbalanced mixture of amino acids that cannot be used for protein synthesis. 

---