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TreatmentsofNFkB - Inhibition of Nuclear Factor Kappa B(NF...

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T he application of anti-inflammatory therapies began thousands of years ago with the use of readily available natural resources. It is only recently, however, that the cellular and molecular mechanisms of inflammation have been appreciated sufficiently to design anti-inflammatory strategies with limited side effects. For example, salicylates and glucocorticoids, two widely used anti-inflammatory drug classes, are now known to inhibit the activation of NF- k B, a transcription factor that regulates the inducible expression of a wide range of proinflammatory mediators. New generations of NF- k B–targeting anti-inflammatory agents that are specific, efficacious, and cost-effective may therefore complement or replace current therapies. In this review, we describe various classes of NF- k B inhibitors and discuss important unresolved issues regarding their use. 22 Inhibition of Nuclear Factor Kappa B (NF- k B): An Emerging Theme in Anti-Inflammatory Therapies Fulvio D’Acquisto, Michael J. May, and Sankar Ghosh Section of Immunobiology and Department of Molecular Biophysics and Biochemistry Howard Hughes Medical Institute Yale University School of Medicine New Haven, CT 06510 In response to a variety of extracellular proinflammatory signals, nuclear factor (NF)- k B is translocated from the cell cytoplasm into the nucleus. The cells shown above have been treated with TNF- a , in response to which NF- k B (stained red) becomes concentrated in cell nuclei so as to activate the transcription of numerous genes that support an inflammatory response.
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INTRODUCTION On January 23, 1899, the dye factories of Friederich Bayer and Co. commercialized one of its most promising pain-relieving drugs (acetylsalicylic acid; ASA) under the name Aspirin (derived from “A” for acetyl, and “spirin” for spireic acid, a synonym of salicylic acid). However, the therapeutic uses and medical history of salicylates actually predate Bayer’s product launch by many centuries (1) . For example, in the time of the ancient Greeks, Hippocrates described the use of “lymph,” an extract of willow bark (now known to be a rich source of salicylic acid), for pain relief during labor. Remarkably, over 2000 years later, salicylates remain one of our most widely used anti- inflammatory therapies. In the first century AD , Celsius described the major clinical symptoms of inflammation: dolor (pain), rubor (redness), tumor (swelling), and calor (heat). The molecular mechanisms responsible for the development of these symptoms are now understood to result from the enhanced expression of a subset of genes that normally maintain physiological homeostasis. For example, soluble mediators such as nitric oxide (NO), prostaglandins (PGs), tumor necrosis factor- a (TNF- a ), and interleukin-1 (IL-1) usually play a role in controlling important functions such as the regulation of blood pressure, platelet aggregation, and body temperature. Under pathologically inflammatory conditions, however,
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TreatmentsofNFkB - Inhibition of Nuclear Factor Kappa B(NF...

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