IL-11 receptor

A critical step in radioprotection involves the IL-1 receptors. Monoclonal antibodies to the type 1 IL-1 receptor block IL-l-induced radioprotection (167). Although this receptor is not present on BM cells, it is present on fibroblasts, which suggests that the effects of IL-1 on stem cells maybe largely indirect and mediated by stromal cell activation (168). Anti-IL-1 receptor (type 1) also sensitizes normal mice to the effects of TBI, which suggests that endogenous IL-1 has an intrinsic radioprotective role. IL-6 induction by IL-1, but not CSF levels, is inhibited, which supports the concept that G-CSF and GM-CSF are insufficient by themselves at radioprotecting stem cells and indicates a contributory role for IL-6. Anti-IL-6 antibody blocks IL-1 and TNF-induced radioprotection and also decreases the intrinsic radioresistance of mice, as does anti-TNF- a (169). 

Anti-cytokines (e.g. IL-1, TNFs, IL-1 receptor constructs) Prostaglandins and PG mimetics... 

IL-1 receptor antagonist Anakinra A naturally occurring complete antagonist, effective in rheumatoid arthritis. 

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... 

IL-1 receptor associated kinase family-A with Toll-like receptor signalling. There are four members in this group to date IRAK-1,2,4 and M. They can phosphor-ylate among themselves, as well with other proteins involved in signalling such as TRAF-6. 

Anakinra/Kineret, an IL-1 receptor antagonist approved for use in rheumatoid arthritis, was recently evaluated in a small phase II trial. When initiated within 6 hours after stroke onset, Anakinra treatment yielded promising preliminary results it was deemed safe with demonstrable biologic activity and likely favorable clinical outcome." ... 

IP4 Inositol tetrakisphosphate IPF Idiopathic pulmonary fibrosis IPO Intestinal peroxidase IpOCOCq Isopropylidene OCOCq I/R Ischaemia-reperfusion IRAP IL-1 receptor antagonist protein IRF-1 Interferon regulatory factor 1 la Short-circuit current ISCOM Immune-stimulating complexes... 

Anakinra is a recombinant form of human IL-1 receptor antagonist. Anakinra inhibits the activity of IL-1 by binding to it and preventing cell signaling.28 Patients must administer a subcutaneous injection every day, which may be less desirable than other treatment options. Anakinra may be used in combination with other DMARDs in patients not responding to or unable to tolerate DMARDs or TNF antagonists.21 Anakinra should not be used in combination with TNF antagonists due to the increased risk of infection.21... 

IL-ip is a well documented sleep factor (reviewed by Obal Krueger, 2003). Its administration increases sleep, its blockade decreases sleep and sleep rebound, and its transcription increases during waking. IL-1 receptor knock-out mice sleep less. Local application of IL-1 p in POA also stimulates NREM sleep. We examined the effects of local administration of IL-1 p and an antagonist through microdialytic application adjacent to lateral POA neurons (Alam et at, 2004). Neuronal activity is recorded within 0.5-1.0 mm of a microdialysis membrane in unrestrained rats. IL-ip potently inhibited the activity of 79% of wake-active neurons. The inhibitory response to IL-ip of wake-active neurons could be blocked by pre-treatment with IL-lra, an IL-ip antagonist. IL-ip application also excited some sleep-active neurons, but this response was inconsistent. 

In addition to IL-la and -1(3, a third IL-l-like protein has been identified, termed IL-1 receptor antagonist (IL-IRa). As its name suggests, this molecule appears to be capable of binding to the IL-1 receptors without triggering an intracellular response. 

Kineret is the tradename given to a recently approved product based on the latter strategy. Indicated in the treatment of rheumatoid arthritis, the product consists of a recombinant form of the human IL-1 receptor antagonist. The 17.3 kDa, 153 amino acid product is produced in engineered E. coli and differs from the native human molecule in that it is non-glycosylated and contains an additional N-terminal methionine residue (a consequence of its prokaryotic expression system). 

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. 

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... 

Sunyer T, Lewis J, Colbn-Osdoby P, Osdoby P (1999) Estrogen s bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells. J Clin Invest 103 1409-1418... 

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... 

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. 

Nesic, O. et al. IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J. Neurotrauma 18, 947, 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. 

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