Interleukins antagonists

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 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... 

Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, RothweU NJ, Tyrrell PJ. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005 76 1366-1372. 

The purported prophylactic use of Japanese herbal medicines to combat neuronal ageing has been related to their free-radical scavenging activity (Hiramatsu a al., 1992). Inhibition of the pro-inflammatory effects of cytokine interleukin-1 by recombinant endogenous interleukin-1 receptor antagonist in experimental rats is associated with alleviation of excitotoxic neuronal damage, an action which has also been related to the antiinflammatory effect of lipocortin 1 (Relton and Roth well, 1992). 

Relton, J.K. and Rothwell, N.J. (1992). Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damr e in the rat. Brain Res. Bull. 29, 243-246. 

IL-Ia. IL-1 8 Interleukin-la, -1(3 ILR Interleukin receptor IL-IR, IL-2R IL-3R - IL-6R Interleukin-1 - 6 receptors IL-lRa Interleukin-1 receptor antagonist... 

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

BUN, blood urea nitrogen Cl, calcineurin inhibitor CSA, cyclosporine IL-2RA, interleukin 2 receptor antagonist LFTs, liver function tests MMF, mycophenolate mofetil OKT-3, muronomab-CD3 RATG, rabbit antithymocyte immunoglobulin ... 

ATC, lymphocyte immune globulin, antithymoglobulin equine AZA, azathioprine BUN, blood urea nitrogen CSA, cyclosporine Cl, gastrointestinal IL-2RA, interleukin 2 receptor antagonist MMF, mycophenalate mofetil OKT-3, muronomonab-CD3 PRED, prednisone SCr, serum creatinine SRL, sirolimus TAC, tacrolimus WBC, white blood cell. 

D13. van Deuren, M., Kinetics of tumour necrosis factor-alpha, soluble tumour necrosis factor receptors, interleukin 1 -beta and its receptor antagonist during serious infections. Eur. J. Clin. Microbiol. Infect. Dis. 13,12-16 (1994). 

Ohlsson, K., Bjorn, P., Bergenfeldt, M Hageman, R., and Thompson, R.C., Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348,550-552 (1990). 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Sepsis involves a complex interaction of proinflammatory (e.g., tumor necrosis factor-a [TNF-a] interleukin [IL]-1, IL-6) and antiinflammatory mediators (e.g., IL-1 receptor antagonist, IL-4, and IL-10). IL-8, plateletactivating factor, and a variety of prostaglandins, leukotrienes, and thromboxanes are also important. 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

A series of 3,5-diarylisoxazole and 3,5-diaryl-l,2,4-oxadiazole derivatives, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists, 456 (Ar = 4-FC6H4), have been identified as IL-8 inhibitors. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced... 

Chang, B. S., Fuscher, N. L. The development of an efficient single-step freeze-drying cycle for interleukin-1 receptor antagonist formulation. Pharm. Res. vol. 12, No. 6, p. 831-837, 1995... 

Based upon recent controlled studies, there is considerable evidence that opioids such as morphine induce substantial effects on immune status. For example, it has been shown that morphine administration is associated with alterations in a number of immune parameters, such as natural-killer cell activity [12,13], proliferation of lymphocytes, [13, 14] antibody production [15,16], and the production of interferon [17]. Studies in our laboratory have shown that acute morphine treatment in rats suppresses splenic lymphocyte proliferative responses to both T- and B-cell mitogens, splenic natural-killer cell activity, blood lymphocyte mitogenic responsiveness to T-cell mitogens, and the in vitro production of the cytokines interleukin-2 and interferon-y [18-22], Furthermore, the immune alterations induced by morphine are dose-dependent and antagonized by the opioid-receptor antagonist, naltrexone (e.g., [22]). 

Suzuki, K. et al. Overexpression of interleukin-1 receptor antagonist provides cardioprotec-tion against ischemia-reperfusion inj ury associated with reduction in apoptosis. Circulation 104,1308, 2001. 

Horai, R. et al., Production of mice deficient in genes for interleukin (IL)-la, IL-ip, and IL-1 receptor antagonist shows that IL-lp is crucial in turpentine-induced fever development and glucocorticoid secretion, J. Exp. Med., 187, 1463, 1998. 

In addition to directly eliciting cell chemotaxis and free-radical production, PAF can also induce the release of various inflammatory cytokines, amongst which tumour necrosis factor (TNF) is of particular importance [ 312 ]. We have recently shown that PAF stimulates TNF production from peripheral blood derived monocytes and at picomolar concentrations amplifies lipopoly-saccharide (LPS)-induced TNF production, effects inhibited by various PAF antagonists [313]. PAF also acts synergistically with interferon-y (IFN-y) to increase the monocyte cytotoxicity. Furthermore, PAF can modulate the production of both interleukin 1 and interleukin 2 (IL-1, IL-2) from rat monocytes and lymphocytes, respectively [222, 223], cytokines which in turn elicit the release of other mediators and growth factors. 

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. 

Vannier E, Dinarello CA Histamine enhances interleukin (IL)-l-induced IL-1 gene expression and protein synthesis via Hj receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist. J Clin Invest 1993 92 281-287. 

Kastrati A, Koch W, Berger PB, et al. Protective role against restenosis from an interleukin-1 receptor antagonist gene polymorphism in patients treated with coronary stenting. J Am Coll Cardiol 2000 36 2168-2173. 

Pharmacology Anakinra is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1 Ra). Anakinra differs from native human IL-IRa in that it has a single methionine residue at its amino terminus. It is produced by recombinant DNA technology using an Escherichia coli bacterial expression system. 

Concurrent administration of etanercept (another TNF -blocking agent) and anakinra (an interleukin-1 antagonist) has been associated with an increased risk of serious infections, and increased risk of neutropenia and no additional benefit compared with these medicinal products alone. Other TNF -blocking agents (including infliximab) used in combination with anakinra also may result in similar toxicities. 

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