Interleukin inhibition

The beneficial action of triamcinolone appears to be related to its inhibition of synthesis of inflammatory mediators (prostaglandins and interleukins), inhibition of the VEGF gene, and improved stability of the blood-retinal barrier. The rise in intraocular pressure typically occurs in 40% to 50% of patients but is controllable with one or two topical antiglaucoma agents. Other complications of IVTA include ptosis, endophthalmitis, accelerated development of cataract, and retinal detachment. The most worrisome compUcation is infectious endophthalmitis, but the incidence of cases is quite low. 

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. 

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

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. 

In conclusion, IFNs have proven to be invaluable tools in the fight against chronic viral hepatitis. In these indications, their antiviral properties play a major role and it remains unclear whether their immunomodulatory properties are also important. Disappointing results obtained with purely immunomodulatory molecules, such as interleukins or Toll-like receptor agonists suggest that, if immunomodulation plays any role, potent inhibition of viral replication is also needed. The role of IFNs in the treatment of viral infections other than hepatitis B and C remains elusive. 

Inhibition of human allergic T-helper type 2 immune responses by induced regulatory T cells requires the combination of interleukin- 10-treated dendritic cells and transforming growth factor-p for their induction. Clin Exp Allergy 2006 36 1546-1555. 

Marshall JS. Leal-Berumen I. Nielsen L. Glibetic M. Jordana M Interleukin (IL)-IO inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. J Clin Invest 1996 97 1122-1128. 

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. 

MI Myocardial ischaemia MIF Migration inhibition factor mIL Mouse interleukin MI/R Myocardial ischaemia/ reperfiision MIRL Membrane inhibitor of reactive lysis... 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Boyle EM, Jr., Kovacich JC, Hebert CA, et al. Inhibition of interleukin-8 blocks myocardial ischemia-reperfusion injury. J Thorac Cardiovasc Surg 1998 116(1) 114-121. 

Arenberg DA, Kunkel SL, Polverini PJ, Glass M, Burdick MD, Stricter RM. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 1996 97(12) 2792-2802. 

Interleukin-10 (IL-10) affects antigen presentation capacity but also interferes with many other functions of monocytes and macrophages (Table 2) (F8). In vitro, IL-10 is a potent inhibitor of cytokine production, including production of TNF, IL-1, IL-6, and IL-8 by LPS-activated monocytes/macrophages (F8). It also inhibits tissue factor-dependent procoagulant activity induced by LPS in human... 

D19. Dinarello, C. A., Okusawa, S., and Gelfland, J. A., Interleukin-1 induces a shock-like state in rabbits Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. In Molecular and Cellular Mechanisms of Septic Shock. Alan R. Liss, New York, 243-263... 

P16. van der Poll, T., Coyle, S. M., Barbosa, K., Braxton, C. C., and Lowry, S. F., Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin-10 production during human en-dotoxemia. J. Clin. Invest. 97,713-719 (1996). 

P20. Pradier, O., Gerard, C., Delvaux, A., Lybin, M., Abramowicz, D., Capel, P., Velu, T., and Goldman, M Interleukin-10 inhibits the induction of monocyte procoagulant activity by bacterial lipopoysaccharide. Eur. J. Immunol. 23,2700-2703 (1993). 

The ability of natural products to inhibition of topoisomerase and precipitate apoptosis mentioned in this chapter are two abilities among several others, of which inhibition of microtubule formation, inhibition of DNA polymerase, protein kinases, protein phosphatase and aromatase, and the use of cytokines, interleukins, and tumor necrosis factor and yet uncovered cellular targets. 

Kelly, ME, Clay, MA, Mistry, MJ, Hsieh-Li, HM, and Harmony, JA, 1994. Apolipoprotein E inhibition of proliferation of mitogen-activated T lymphocytes Production of interleukin 2 with reduced biological activity. Cell Immunol 159, 124—139. 

Yoshimoto, T., Okamura, H., Tagawa, Y., Iwakura, Y. and Nakanishi, K. (1997) Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-y production from activated B cells. Proceedings of the National Academy of Sciences USA 94, 3948-3953. 

Iijima, H., Takahashi, I., Kishi, D., Kim, J.K., Kawano, S., Hori, M. and Kiyono, H. (1999) Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice. Journal of Experimental Medicine 190, 607-615. 

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