Antiinflammatory action of glucocorticoids--new mechanisms for old drugs.

nflammation is a reflexive response to infection, the binding of antibodies to antigens within the body, mechanical irritation, or injury. 1 Mi- crobes that breach epithelial barriers, 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 media- tors with acute effects on the vasculature. Localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leuko- cytes into the affected tissue produce the classic signs of inflammation: calor, dolor, rubor, tumor, and functio laesa. A positive feedback loop initiates the production of ad- ditional inflammatory cytokines once infiltrating leukocytes become activated. Antiin- flammatory homeostatic mechanisms reverse these processes as the infectious agent is cleared by the innate and adaptive immune systems. The hypothalamic-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 aller- gies, asthma, autoimmune diseases, and sepsis are a major cause of illness and death. Asthma affects approximately 21.9 million adults and 8.9 million children in the Unit- ed States alone. The prevalence of autoimmune diseases, which affect 8.5 million Americans, 3,4 is also noteworthy. Rheumatoid arthritis, Graves' disease, glomerulone- phritis, type 1 diabetes mellitus, multiple sclerosis, thyroiditis, pernicious anemia, sys- temic lupus erythematosus, psoriasis, and vitiligo account for most of these autoim- mune 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 inflam- matory 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 re- pair, osteoporosis, and metabolic disturbances. All these harmful properties contrain- dicate prolonged glucocorticoid therapy. Here, we review mechanisms whereby gluco- corticoids inhibit inflammation and the therapeutic limitations of these hormones. We then provide a prospectus for research on drugs that dissociate the beneficial and det- rimental effects of glucocorticoids.