Other cytokines

Other cytokines synthesised by activated neutrophils (but not bloodstream neutrophils) include interferon-a G-CSF and M-CSF. Interferon-a expression is stimulated by exposure of blood neutrophils to G-CSF (incubation times 3 h are required), but expression of this cytokine is not activated by exposure to either LPS or fMet-Leu-Phe. G-CSF induces 0.95- and 1.2-kb mRNA molecules, the latter transcript containing the message plus a 3 noncoding region. Synthesis of interferon-a protein (as determined by a radioimmunoassay) requires incubation times in excess of 6 h, and the functions of this cytokine include inhibition of neutrophil-colony formation and platelet formation in vitro. 

GM-CSF stimulates the expression of both G-CSF and M-CSF by blood neutrophils. These latter cytokines play important roles in haematopoiesis (Chapter 2), and G-CSF can also prime mature neutrophil function (see 7.2.1). Levels of production of these CSFs are about five to ten times lower than those produced by monocytes (on a per-cell basis). 

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Interleukin-1 OC and (3. IL-1 has radioprotective activity toward BM and other tissues (151,164). IL-1 is produced in response to endotoxin, other cytokines, and microbial and viral agents, primarily by monocytes and macrophages. Other nucleated cells can also produce it. IL-1 appears to play an important role in the regulation of normal hemopoiesis directly by stimulating the most primitive stem cells and indirectly by stimulating other hemopoietic factors, including G-CSF, GM-CSF, M-CSF, and IL-6. 

Although this may suffice, additional factors contribute to this process. Activated T-lymphocytes secrete amongst other cytokines also interferon y which... 

NF-IL6 is a nuclear factor for interleukin-6, a transcription factor which is activated by IL-6 and other cytokines and stimulates stress protein gene expression. 

Rheumatoid synovial cells produce a broad range of cytokines (Brennan et al., 1991). The formation of IL-la, IL-1 /3, GM-CSF, G-CSF, TNFa and other cytokines may be under the direct influence of ox-LDL and/or... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Erythropoiesis is a process that starts with a pluripotent stem cell in the bone marrow that eventually differentiates into an erythroid colony-forming unit (CFU-E)4 (Fig. 63-1). The development of these cells depends on stimulation from the appropriate growth factors, primarily erythropoietin. Other cytokines involved include granulocyte-monocyte colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). Eventually, the CFU-Es differentiate into reticulocytes and cross from the bone marrow into the peripheral blood. Finally, these reticulocytes mature into erythrocytes after 1 to 2 days in the bloodstream. Throughout this process, the cells gradually accumulate more hemoglobin and lose their nuclei.4... 

T lymphocytes become activated over the course of 3 to 4 weeks, producing interferon-y (IFN-y) and other cytokines. These stimulate microbicidal macrophages to surround the tuberculous foci and form granulomas to prevent further extension.15 At this point, the infection is largely under control, and bacillary replication falls off dramatically. Any remaining mycobacteria are believed to reside primarily within granulomas or within macrophages that have avoided detection and lysis. Over 1 to... 

It has already been noted that the phenotype of an acquired immune response is considered to reflect the early cytokine environment in which naive CD4+ T cells interact with antigen. Again, it has been suggested, for example, that early exposure to IL-4 can push an immune response in a Th-2 direction (Swain et al., 1990). We therefore investigated (by ELISA) whether ES-62 was able spontaneously to induce IL-4 secretion in naive murine spleen cells (48 h exposure). Ironically, given that the molecule induces a Th-2 antibody response and seems to be able to induce the release of a number of other cytokines, IL-4 was not detected (Harnett et al., 1999a). It was noted, however, that IL-4 was produced by spleen cells from mice that had been pre-exposed to ES-62. This established Th-2 phenotype is consistent with the antibody data. 

In contrast, some cytokines (e.g. some CSFs and EPO) appear to be expressed constitutively. In yet other instances cytokines such as PDGF and TGF-P are stored in cytoplasmic granules and can be rapidly released in response to appropriate stimuli. Other cytokines (mainly ones with growth factor activity, e.g. TGF-P, FGF and IL-1) are found bound to the extracellular matrix in connective tissue, bone and skin. These are released, bringing about a biological response upon tissue injury. 

As was the case for most other cytokines, medical appraisal/use of IL-2 was initially impractical due to the minute quantities in which it is normally produced. Some transformed cell lines, most notably the Jurkat leukaemia cell line, produces IL-2 in increased quantities, and much of the IL-2 used for initial characterization studies was obtained from this source. Large-scale IL-2 production was made possible by recombinant DNA technologies. Although the IL-2 gene/cDNA has now been expressed in a wide variety of host systems, it was initially expressed in E. coli, and most products being clinically evaluated are obtained from that source. As mentioned previously, the absence of glycosylation on the recombinant product does not alter its biological activity. 

Like all other cytokines, administration of IL-2 can induce side effects that can be dose limiting. Serious side effects, including cardiovascular, hepatic or pulmonary complications, usually necessitate immediate termination of treatment. Such side effects may be induced not only directly by IL-2, but also by a range of additional cytokines whose synthesis is augmented by IL-2 administration. These cytokines, which can include IL-3, -4, -5 and -6, as well as TNF and IFN-y, also likely play a direct role in the overall therapeutic benefits accrued from IL-2 administration. 

The direct induction of immunostimulatory substances, most notably interleukins and other cytokines. 

Other Cytokines including interleukins 1 (3,2,3,4,5,7,9, 11 and 12 have been reported to exhibit neurotrophic activities [17]. The concentrations of these cytokines in... 

Once T cells are activated, they migrate from lymph nodes and the bloodstream into skin and secrete various cytokines (e.g., interferon % interleukin 2 [IL-2]) that induce the pathologic changes of psoriasis. Local keratinocytes and neutrophils are induced to produce other cytokines, such as tumor necrosis factor-a (TNF-a), IL-8, and others. 

Vitamin D and its analogs inhibit keratinocyte differentiation and proliferation and have antiinflammatory effects by reducing IL-8, IL-2, and other cytokines. Use of vitamin D itself is limited by its propensity to cause hypercalcemia. 

TNF-a is considered the primary mediator of sepsis, and concentrations are elevated early in the inflammatory response during sepsis, and there is a correlation with severity of sepsis. TNF-a release leads to activation of other cytokines associated with cellular damage and it stimulates release of arachidonic acid metabolites that contribute to endothelial cell damage. IL-6 is a more consistent predictor of sepsis as it remains elevated for longer periods of time than does TNF-a. 

Malarkey, W.B. and Zvara, B.J., Interleukin-1-6 and other cytokines stimulate ACTH release from cultured pituitary cells of patients with Cushing s Disease, J. Clin. Endocrinol. Metab., 69, 196, 1989. 

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