Cytokine receptor antagonists

AF 11377 is a 15 residue peptide that acts as a CYTOKINE RECEPTOR ANTAGONIST both in terms of competing for binding with IL-1 at the IL-lRl receptor subtype and also blocks functional responses to IL-1 in human and monkey cells, afloqualone [inn, jan] is a quinazolinone derivative. It is a centrally acting SKELETAL MUSCLE RELAXANT. 

CYTOKINE RECEPTOR ANTAGONISTS act to inhibit at one or more of the extremely diverse group of sites... 

In addition to inhibiting cytokine synthesis by glucocorticoids, cytokine effects can be prevented by scavenging the cytokine either with neutralizing antibodies or soluble receptors or by blocking the respective cytokine plasma membrane receptors with blocking antibodies or receptor antagonists. 

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). 

Antiinflammatory mediators including IL-1 receptor antagonist, IL-4, and IL-10 are also produced in sepsis and inhibit production of proinflammatory cytokines. The net effect can vary depending on the state of activation of the target cell, and the ability of the target cell to release mediators that... 

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... 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

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]). 

The IL-1 receptor antagonist (IL-lra) is present in human milk. IL-lra limits inflammation by competing with IL-1 (pro-inflammatory cytokine) for receptor binding (Dinarello, 1995). The reduced inflammatory response in rats with colitis fed human milk compared to chow or formula was similar to the inflammatory response in rats fed infant formula supplemented with IL-lra (Grazioso et al., 1997). These results suggest that the IL-lra content of human milk contributes to its anti-inflammatory properties. 

Reznikov, L.L., A.J. Puren, G Fantuzzi, H. Muhl, L. Shapiro, D.Y Yoon, D.L. Cutler, and C.A. Dinarello, Spontaneous and inducible cytokine responses in healthy humans receiving a single dose of IFN-alpha2b increased production of interleukin-1 receptor antagonist and suppression of IL-1-induced IL-8. J Interferon Cytokine Res, 1998.18(10) 897-903. 

Interleukin-1 (11-1) plays a key role in the body s response to microbes and to tissue injury.210,211 It actually consists of three similar proteins, Il-la, IL-1 5, and 11-1 receptor antagonist. The first two are the active cytokines with a wide range of effects among... 

Cytokine receptors compete for a limited amount of JAK as observed in the IL-12/ IFN-aRl system. A receptor without a kinase is unable to send signals and may dilute the effects of a cytokine by serving similar to an artificial receptor used clinically as decoys as is the case in IL-4 antagonist in the treatment of asthma. 

The studies from our group showed that curcumin inhibited pancreatic cancer in patients. Twenty-five patients were enrolled in this study. Patients received 8 g of curcumin orally daily until disease progression, with restaging every 2 months. Serum cytokine levels for IL-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell (PBMC) expression of NF-kB and COX-2 were monitored. Out of 25 patients, 21 were evaluable for... 

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