Cytokines transcriptional regulation activation

Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function (see Chapter 2). Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the... 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

Activation of STATs is transient, like that of other transcriptional regulators. When cytokine signalling is terminated, the concentrations of active STATs in the nucleus decline, because STATs are either inactivated by dephosphorylation or removed by proteolysis, or both. Accordingly, the half-life of STAT 1 can be prolonged by preventing dephosphorylation, through inhibition of phosphotyrosine phosphatases. Finally, there are inhibitors of JAK/STAT signalling that are induced by STATs. 

Tyrosine kinase-associated receptors called Jak-STAT receptors are often used by cytokines to regulate the proliferation of certain cells involved in the immune response (see Fig. 11.9B). The receptor itself has no intrinsic kinase activity but binds (associates with) the tyrosine kinase Jak (janus kinase). Their signal transducer proteins, called STATs (signal transducer and activator of transcription), are themselves gene-specific transcription factors. Thus, Jak-STAT receptors have a more direct route for propagation of the signal to the nucleus than tyrosine kinase receptors. 

The high concentration of NO which is induced by activated macrophages may be cytostatic or cytotoxic for tumor cells. Lipopolysaccharide (LPS) or some cytokines such as TNF-a and IFN-y can efficiently regulate iNOS transcription by activation of nuclear factors such as NF-kB and AP-1. Thus, macrophage activation to induce high concentration of NO by LPS or some cyotokines is a candidate for anti-tumor therapy. 

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