Interleukin ligands

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

The first etCCR application has been reported for a partially C— N-labeled phosphotyrosine peptide derived from interleukin-4 receptor ligated to STAT-6 [107] and subsequent studies involve nucleotide cofactors ligated to human recombinant deoxycytidine kinase [108] and epothilone A bound to tubulin [109]. Since etCCR usually involves isotope-labeling schemes for the ligand, its applicability is limited to specific molecular classes. 

FIGURE 27-3 Neurotrophic cytokines and their receptors. Neurotrophic cytokines are related to IL6 and bind to cell surface receptor complexes that share a common structural organization. The four ligands interchangeably employ two distinct receptor subunits, leukemia inhibitory factor receptor 3 (LIF-Rpt) andgpl30, and some employ a ligand-specific a subunit. CNTF-R, ciliary neurotrophic factor CT-fR.cardiotrophin 1 receptor IL6-R, interleukin-6 receptor. 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-lbeta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25 255-259... 

Cheung J, Mak YT, Papaioannou S, Evans BA, Fogelman I, Hampson G (2003) Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol 177 423-433... 

Many extracellular agents or inducers of cell injury or stress such as tumor necrosis factor alpha (TNFa), fas ligands, Y-interferon, interleukin-1... 

Carson W-E, Fehniger TA, Caligiuri MA CDSe " natural killer cell subsets characterization of distinct functional responses to interleukin-2 and the c-kit ligand. Fur J Immunol 1997 27 354-360. 

Fig. 11.1. Principle of an immunological synapse. Possibilities for communication between B and T cells during an immune response. Antigenic peptides are presented by the MHC complex class II at the surface of the B cell. The antigens are recognized and bound by T cell receptors of the T cell. The T cell receptor is activated and sets a signal chain in motion that leads to activation of the expression of cytokines, such as IL-2. The cytokine is secreted, and binds and activates a cytokine receptor on the B cell. TNFa is shown as another example of a ligand-receptor system. TNFa communicates, as a membrane-bound ligand, with a corresponding receptor on the surface of the B cell. The interactions shown take place in a narrow spatial region between B and T cells, which is why this system is referred to as an immunological synapse. TNF tumor necrosis factor MHC major histocompatibility complex IL-2 interleukin 2.

A. General description Denileukin dif-titox is a recombinant, DNA-derived, interleukin-2 receptor specific ligand, cytotoxic fusion protein consisting of diphtheria toxin fragments A and B fused to interleukin-2. It is produced by expression of a recombinant fusion protein in Escherichia coli that contains nucleotide sequences for human interleukin-2, and sequences for the enzymatically active fragment A of diphtheria toxin and the membrane-translocating portion of diph-... 

A close relative of immunotoxins is the growth factor fusion toxin, in which antibody is replaced with a ligand or growth factor to provide selectively of the toxin domain in immunotoxin. One such molecule, containing human interleukin-2 (IL-2) fused to truncated diphtheria toxin (denileukin diftitox or Ontak), was approved by the FDA in 1999. 

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