Interleukin synthesis

Auranofin, a gold salt currently used for therapy of chronic inflammation associated with rheumatoid arthritis, has been reported to induce several stress proteins and inhibit interleukin synthesis in human peripheral blood monocytes (Caltabiano et al. 1986b Schmidt and Abdulla 1988). 

This drug also is reported to activate macrophages, to iaduce polyclonal B-ceU activation as well as enhance specific antibody production m vivo, and to iaduce the synthesis of iaterferon and interleukin 1 (52). The iaduction of these important cytokiaes (and others) largely accounts for the profile of biological activity displayed by the pyrimidinones. Bropirimine is currentiy ia clinical evaluation for cancer, arthritis, and immunorestoration ia AIDS patients. 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

Madindoline A (7) and B (ent-8) are potent inhibitors of interleukin 6. In a total synthesis [21] that also intended to determine the relative and absolute configurations of these novel antibiotics, the densely functionalized cyclopen-tene-l,3-dione ring of 7 and 8 was elaborated via RCM of diene-diol 2 (Scheme 1). 

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

Biber K, Zuurman MW, Dijkstra IM, Boddeke HW (2002) Chemokines in the brain neuroimmunology and beyond. Curr Opin Pharmacol 2 63-68 Blasko 1, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B (2000) Costimulatory effects of interferon-gamma and interleukin-1 beta or tumor necrosis factor alpha on the synthesis of Abetal-40 and Abetal-42 by human astrocytes. Neurobiol Dis 7 682-689... 

Evidence for a neuroimmunological involvement in Alzheimer s disease is accumulating. Activation of the complement cascade by beta amyloid (Rogers et al., 1992), the recruitment, proliferation and activation of microglia in intimate juxtaposition to the senile plaques (Davis et al., 1992), and the increased synthesis of microglia-derived pro-inflammatory cytokine interleukin-1 (Griffin et al., 1989) is indicative of a chronic inflam-... 

O T cells are the chief components initiating the immune response against the allograft. The activity of T cells is mediated largely through the synthesis and release of interleukin-2 (IL-2). 

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. 

Kraan MC, Patel DD, Haringman JJ, et al. The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res 2001 3(1) 65-71. 

Z8. Zuckerman, S. H., Shellhaas, J., and Butler, L. D., Differential regulation of lipopolysaccharide-induced interleukin I and tumor necrosis factor synthesis Effects of endogenous and exogenous glucocorticoids and the role of the pituitary-adrenal axis. Eur. J. Immunol. 19,301-305 (1989). 

Lindholm, D., Heumann, R., Meyer, M. and Thoenen, H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 330 658-659, 1987. 

Interleukin-6 (IL-6) is a member of the gpl30 cytokine family and is con-stitutively produced by several cells of bone microenvironment, particularly by osteoblasts and their precursors (Heymann et al. 2000). The main function in bone is on OCS and bone resorption, and its effects are connected to those of IL-1, TNF-a, and PTHrP. IL-6 induces osteoclastlike formation by inducing IL-1 synthesis, and the addition of anti-IL-1 inhibits osteoclast formation by IL-6 (Kurihara et al. 1990). Moreover, IL-6 mediates the effects of TNF-a and enhances PTHrP-induced hypercalcemia and bone resorption by increasing the osteoclast progenitor pool and differentiation into mature osteoclasts (Devlin et al. 1998). 

Synthesis of a number of O-glycosides (such as 131 -134) having different chain lengths between amino acids Ax and A10, which are part of interleukin-2, was accomplished by application of the Fmoc group in combination with the rm-butyl ester (77,78). 

Lee, H., Shi, W., Tontonoz, P., Wang, S., Subbanagouder, G., Hedrick, C.C., Hama, S., Borromeo, C., Evans, R.M., Berliner, J.A., and Nagy, L, 2000, Role for peroxisome prohferator-activated receptor [alpha] in oxidized phospholipid-induced synthesis of monocyte chematachc protein-1 and interleukin-8 by endothehal cehs, Circ. Res. 87 516-521. 

Lubberts E, Joosten LA, van de Loo FA, van den Gersselaar LA, van den Berg WB Reduction of interleukin-17-induced inhibihon of chondrocyte proteoglycan synthesis in intact murine articular carhlage by interleukin-4. Arthritis Rheum 2000 43 1300-1306. 

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. 

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