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new england journal



review article

mechanisms of disease

Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs
Turk Rhen, Ph.D., and John A. Cidlowski, Ph.D.


nflammation is a reflexive response to infection, the binding of antibodies to antigens within the body, mechanical irritation, or injury.1 Microbes that breach epithelialbarriers, for instance, directly activate complement and toll-like receptors, two principal components of the innate immune system. The activation of these sentinels triggers the synthesis and release of inflammatory mediators with acute effects on the vasculature. Localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leukocytes intothe affected tissue produce the classic signs of inflammation: calor, dolor, rubor, tumor, and functio laesa. A positive feedback loop initiates the production of additional inflammatory cytokines once infiltrating leukocytes become activated. Antiinflammatory homeostatic mechanisms reverse these processes as the infectious agent is cleared by the innate and adaptive immune systems. Thehypothalamic–pituitary– adrenal axis and glucocorticoids in particular are essential in limiting and resolving the inflammatory process.2 Whereas restricted inflammation is beneficial, excessive or persistent inflammation incites tissue destruction and disease. Together, inflammatory disorders such as allergies, asthma, autoimmune diseases, and sepsis are a major cause of illness and death. Asthma affectsapproximately 21.9 million adults and 8.9 million children in the United States alone. The prevalence of autoimmune diseases, which affect 8.5 million Americans,3,4 is also noteworthy. Rheumatoid arthritis, Graves’ disease, glomerulonephritis, type 1 diabetes mellitus, multiple sclerosis, thyroiditis, pernicious anemia, systemic lupus erythematosus, psoriasis, and vitiligo account for most of theseautoimmune diseases. Sepsis is fatal for roughly 30 percent of the 700,000 patients affected annually in the United States.5-7 Glucocorticoids are indicated for the treatment of many of these diverse conditions. The efficacy of glucocorticoids in alleviating inflammatory disorders results from the pleiotropic effects of the glucocorticoid receptor on multiple signaling pathways. Pleiotropy can,however, also have adverse effects: growth retardation in children, immunosuppression, hypertension, inhibition of wound repair, osteoporosis, and metabolic disturbances. All these harmful properties contraindicate prolonged glucocorticoid therapy. Here, we review mechanisms whereby glucocorticoids inhibit inflammation and the therapeutic limitations of these hormones. We then provide a prospectus forresearch on drugs that dissociate the beneficial and detrimental effects of glucocorticoids.

From the Department of Biology, University of North Dakota, Grand Forks (T.R.); the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, N.C. (J.A.C.); and the Department of Health and Human Services, National Institutes of Health, Bethesda, Md.(J.A.C.). Address reprint requests to Dr. Cidlowski at the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr., Research Triangle Park, NC 27709, or at cidlows1@niehs. N Engl J Med 2005;353:1711-23.
Copyright © 2005 Massachusetts Medical Society.

b as ic actions of endogenous glucocorticoids
Thehypothalamic–pituitary–adrenal axis plays a central role in regulating signaling by the glucocorticoid receptor, which is expressed in virtually all cells. In brief, neural, endocrine, and cytokine signals converge at the level of the periventricular nucleus of the

n engl j med 353;16

october 20, 2005


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