The Interleukins

Aldesleukin is indicated for the treatment of metastatic renal cell carcinoma in adults. It is also indicated for the treatment of metastatic melanoma in adults. Research is under way on the use of aldesleukin for the tieatmcni of various cancers (including head and neck cancers), treatmeni of acute myelogenous leukemia, and adjunct therapy in the treatment of Kapasi s sarcoma. Renal and hepatic Unction is typically impaired during therapy with aldesleukin, so interaction with other drugs that undergo elimination by these organs is po.ssible. 

sleukin is supplied as a powder for solution. After reconstitution, the. solution. should not be shaken. The preparation is solubilized with. sodium dodecyl sulfate in a phos- 

Denileukin diftitox is indicated for the treatment of persistent or recuirent cutaneous T-cell lymphoma who.se malignant cells express the CD25 component of the IL-2 receptor. 

Denileukin diftitox is supplied as a frozen solution in water for injection. It should be stored at -I0°C or colder. It IS suggested that the vials be thawed in a refrigerator at 3 to xT for less than 24 hours or at nKini temperature for 

I to 2 hours. Preptued solutions should be u.sed within 6 hours. The dmg is administered by IV infusion from a bag or timnigh a syringe pump. 

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Recombinant human DL-1 receptor antagonist (Anakinra, Kineret ) blocks the biological activity of interleukin-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. Thereby it reduces the pro-inflammatory activities of IL-1 including cartilage destiuction and bone resorption. Side effects include an increased risk of infections and neutropenia. 

The chimeric human/murine (basiliximab and dacluzi-mab) or murine (inolimomab) monoclonal antibodies are specifically directed against a part (CD25) of the interleukin-2 (IL-2) receptor. Binding of one of these antibodies to CD25 thereby displaces physiological IL-2 and prevents proliferation of activated T-lymphocytes. 

The interleukin-1 (EL-1) family of proteins currently comprises IL-1 a, IL-1 (3, and the IL-1 receptor antagonist (IL-1RA). The biological activities of EL-1 are shared by IL-1 a and IL-1 (3, whereas IL-1RA is a true receptor antagonist. IL-1 is a key player in acute and chronic inflammatory diseases. Whether IL-1 has a role in normal physiology is still unresolved. IL-1 can... 

Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC (2004) Role of the interleukin (lL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of lL-29/interferon-lambda 1 similarities with type I interferon signaling. J Biol Chem 279 ... 

Garcia-Montero AC, Jara-Acevedo M. Teodosio C. et al KIT mutation in mast cells and other bone marrow hematopoietic cell hneages in systemic mast cell disorders a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006 108 2366-2372. Daley T, Metcalfe DD, Akin C Association of the Q576R polymorphism in the interleukin-4 receptor a chain with indolent mastocytosis limited to the skin. Blood 2001 98 880-882. 

Cerretti DP, Kozlosky CJ, Mosley B et al (1992) Molecular cloning of the interleukin-1 beta converting enzyme. Science 256 97-100... 

NF-xB activates genes encoding MHC class I antigens, IL-1, TNFa, IL-6, the interleukin-2 (IL-2) receptor, some acute-phase proteins and the adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) (lademarco... 

The production of a female-influencing secretion from the chin gland of male Plethodontid salamander (P. jordani) points to a similar extension of function by the acquisition of female olfactory sensitivity to an intercellular signal protein. Female receptivity is enhanced by a male cytokine-like compound of the interleukin-6 family, in its released form. Rollman et al. (1999) note that pheromonal activity is a previously unrecognised function for cytokines. 

The interleukin-2 receptor (IL-2R) is important in that the cytokine IL-2, secreted by a subset of T-helper cells, enhances the proliferation of activated T and B cells and increases the cytolytic activity of natural killer (NK) cells and the secretion of IgG. 

Lugli, S.M., Feng, N., Heim, M.H., Adam, M., Schnyder, B., Etter, H., Yamage, M., Eugster, H.P., Lutz, R.A., Zurawski, G. and Moser, R. (1997) Tumor necrosis factor alpha enhances the expression of the interleukin (IL)M receptor alpha-chain on endothelial cells increasing IL-4 or IL-13-induced Stat6 activation. Journal of Biological Chemistry 272, 5487-5494. 

Sorenson, P., Farber, N.M., and Krystal, G. (1986) Identification of the interleukin-3 receptor using an iodinatable, cleavable, photoreacdve cross-linking agent./. Biol. Chem. 261, 9094-9097. 

Most of the interleukins are produced by a number of different cell types. At least 17 different cell types are capable of producing IL-1, and IL-8 is produced by at least 10 distinct cell types. On the other hand, IL-2, -9 and -13 are produced only by T-lymphocytes. 

Nearly all of the interleukins are soluble molecules (one form of IL-1 is cell associated). They promote their biological response by binding to specific receptors on the surface of target cells. Most interleukins exhibit paracrine activity (i.e. the target cells are in the immediate vicinity of the producer cells), although some display autocrine activity (e.g. IL-2 can stimulate the growth and differentiation of the cells that produce it). Other interleukins display more systematic endocrine effects (e.g. some activities of IL-1). 

Table 9.1 Many cell types are capable of producing a whole range of interleukins. T-lymphocytes are capable of producing all the interleukins, with the possible exception of IL-7 and IL-15. Many cell types producing multiple interleukins can also produce additional cytokines. For example, both macrophages and fibroblasts are capable of producing several interleukins, CSFs and PDGF...

The sum total of biological responses induced by the interleukins is large, varied and exceedingly complex. These cytokines regulate a variety of physiological and pathological conditions, including ... 

IL-2, also known as T-cell growth factor, represents the most studied member of the interleukin family. It was the first T-cell growth factor to be identified and it plays a central role in the immune response. It is produced exclusively by T-lymphocytes (especially T-helper cells), in response to activation by antigen and mitogens. 

Martin, M. and Falk, W. 1997. The interleukin-1 receptor complex and interleukin-1 signal transduction. European Cytokine Network 8(1), 5-17. 

The interleukin family of cytokines has been overviewed in Chapter 9, and a number of cytokines are known to influence haemopoiesis. The IL-3 receptor, for example, is found on a wide variety of progenitor haemopoietic cells, and appears to stimulate not only CFU-GEMM, but also the precursor cells of basophils, eosinophils and platelets. The role of IL-11, which also plays a role, was also discussed in Chapter 9. 

Dimarello CA (1994) The interleukin-1 family 10 years of discovery. FASEB J 8 1314-1325... 

Stein B, Yang MX (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol 15 4971-4979... 

Vidigal, P. G., Germer, J. J., and Zein, N. N., Polymorphisms in the interleukin-10, tumor necrosis factor-alpha, and transforming growth factor-betal genes in chronic hepatitis C patients treated with interferon and ribavirin, J. Hepatol., 36, 271, 2002. 

Ness, T.L. et al. Isolation and expression of the interleukin-2 gene from the killer whale, Orcinus orca, Mar. Mamm. Sci, 14, 531, 2000. 

While the majority of attention has focused on peptides contained within the nervous system, two other important methods for delivering peptides to the vicinity of the mast cell have been established (1) peptides produced and secreted by other cells of inflammation that may affect mast-cell function and (2) the local generation of mast-cell-active peptides by secreted enzymes acting on circulating protein precursors. Examples of the former include several, as yet ill-defined, peptide factors and cationic proteins from other immunocompetent cells [66-69], defined lymphokines such as the interleukin-1 [70] and interleukin-3 [71], and tumour necrosis factor [70], Examples of the latter include bradykinin [72] and a recently identified peptide produced by the action of acid proteinases on albumin [73, 74]. 

Thomas, K. M., Taylor, L., Navarro, J. (1991). The Interleukin-8 receptor is encoded by a neutrophil-specific cDNA clone, F3R. J. Biol. Chem. 266,14839-41. 

McColl, S. R., Paquin, R., Menard, C., Beaulieu, A. D. (1992). Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/ macrophage colony-stimulating factor and tumor necrosis factor a. J. Exp. Med. 176, 593-8. 

Meretey K, Falus A. Taga T. Kishimoto T Histamine influences the expression of the interleukin-6 receptor on human lymphoid, monocytoid and hepatoma ceU hnes. Agents Actions 1991 33 189-191. 

Lewis DA, Guzzetta AW, Hancock WS, Costello M. 1994. Characterization of humanized anti-TAC, an antibody directed against the interleukin 2 receptor, using electrospray ionization mass spectrometry by direct infusion, LC/MS, and MS/MS. Anal Chem 66 585. 

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