IL-2 production

Figure 9.3 Activation of T-cells by interaction with macrophage-displayed antigen. Activation results in IL-2 production, which acts in an autocrine manner to stimulate further T-cell growth and division. IL-2 thus represents the major regulatory molecule responsible for stimulation of cell-mediated immunity. Note that it was initially believed that binding of presented antigen alone was insufficient to trigger T-cell activation. It was thought that co-stimulation with IL-1 was reguired. However, the assay used to detect the co-stimulation was found not to be specific for IL-1 alone. The role of IL-1 as a co-stimulator of T-cell activation is now believed to be minimal at most...

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. 

FIGURE 9.2 Regulation of Immunity by lnterleukin-2 (IL-2). IL-2 production by T cells and DCs supports the proliferation of T cells, B cells, T reg cells, and NK cells, in addition to establishing a bias towards a Type 1 T cell response. IL-2 can also activate monocytes and NK cells, resulting in increased cytotoxicity. DC dendritic cell IL-2 interleukin-2 NK natural killer cell. 

Alteration of membrane structure in immune cells by PUFAs can lead to defective signal transduction and decreased function. PUFA treatment of CD3-activated human T cells results in decreased calcium mobilization, proliferation and IL-2 production... 

AS601245 has been reported to be an ATP-competitive inhibitor of JNK1, 2 and 3 with IC50 values = 150, 220 and 70 nM, respectively, with minimal to no activity in a panel of 25 other kinases [48]. In Jurkat T-cells, AS601245 at 10 pM inhibited IL-2 production induced by phorbol-12-myristate-l 3-acetate (PMA) by 90%. The weaker cell activity could be due to poor cell permeability. The oral bioavailability of AS601245 in rats was 38%. In mice, AS601245, when dosed at 60 mg/kg p.o. in a developed arthritis model induced by collagen, showed... 

Nickel significantly enhanced the synthesis and/or secretion of IL-2 by cultured murine splenocytes and also the expression of the receptor for IL-2 [386]. It was also shown [387] that nickel increased IL-2 production in an antigen-specific (ovalbumin) T cell activation system in vitro. 

Cyclosporin A Transplant rejections Depresses T cells inhibits IL-2 production... 

T-cells influence. SSTE and nicotine were incubated in splenic mononuclear cells at concentrations of 1 10 or 1 10 dilutions of STD, or 10 or 100 i.g/mL nicotine, during 4 days of stimulation with anti-CD3. The treatment sustained expression of IL-2, IFN-y, IL-10, and IL-4 cytokine mRNA at 100 i.g/mL nicotine. STD did not exhibit residual expression of cytokine mRNA. Restimulated STD exhibited maximum IL-2, IL-4, IFN- y, and IL-10 mRNA at 48 hours . STE, in splenic mononuclear cell culture at LlOHo 1 10 dilutions, increased IL-2 production and decreased IL-10 at 1 10 dilution. IFN-y production was decreased at all concentrations. STE did not alter IL-4 product ion k P-benzoquinone, a thiol-reactive benzene derivative from cigarette tar, was incubated in human peripheral blood mononuclear cells at a concentration of 10 xM. The treat-... 

Inhibition of interleukin-2 (IL-2) production or action cyclosporin, tacrolimus, rapamycin (sirolimus). 

The introduction of cyclosporin, a peptide derived from a fungus, revolutionised immunosuppressive therapy, and was one of the major influences in the improvement of early graft survival in transplant surgery when introduced in the 1980s. The main action is a relatively selective inhibition of IL-2 production and consequently a decreased proliferation of T cells. A major advantage of cyclosporin is that it does not cause myelosuppression in therapeutic doses. The major side effect is nephrotoxicity, which occurs in about 20% of patients, and about 50% of patients develop moderate hypertension. The other major side effect is hepatotoxicity with cholestasis and hyperbilirubinaemia. 

Fig. 4.1 Mechanism of action of cyclosporine. Cyclosporine readily diffuses into the cytoplasm of the target cells where it binds to cyclophilins. The cyclosporine-cyclophilin complex stably associates with calcineurin and inhibits calcineurin activity. Calcineurin is a Ca2+-dependent enzyme— serine/threonine phosphatase— which after activation by Ca2+, dephosphorylates a cytosolic component of NFAT (NFATc, cytosolic factor of activated T cells). After dephosphorylation, NFATc migrates from the cytoplasm to the nucleus where it associates with NFATn and induces transcription of several cytokine genes including IL-2. Cyclosporine inhibits calcineurin activity after associating with cyclophilins, resulting in the inhibition of IL-2 production and other cytokines (see Color Insert)...

NFATc, and as a result, the transport of NFATc to the nucleus is prevented and consequently its association with NFATn does not proceed (Fig. 4.1). The association of NFATc with NFATn is essential for the initiation of IL-2 production, which is achieved through binding of NFATc-NFATn to the promoter of the IL-2 gene. As a result, IL-2 production is inhibited, which is necessary for the optimal function of the immune response. Cyclosporine does not inhibit cytokine-induced transduction mechanisms and also has no effect on antigen recognition by T cells in the context of MHC molecules. 

Neutral glycosphingolipids block immune cell proliferation and IL-2 production evoked by exposure to pokeweed (aT cell mitogen) (Persat et al., 1996)... 

Antigen inhibition of murine and human splenocyte and PBMC-ConA-induced proliferation and IL-2 production (Wang and McKay, 2005)... 

Barton, K., Muthusamy, N., Chanyangam, M., Fischer, C., Clendenin, C. and Leiden, J. M., 1996, Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominantnegative form of CREB, Nature, 379, pp 81—5. 

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