Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs

Abstract

nflammation is a reflexive response to infection, the binding of antibodies to antigens within the body, mechanical irritation, or injury. 1 Microbes 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 mediators with acute effects on the vasculature. Localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leukocytes 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 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. The hypothalamic-pituitaryadrenal 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 affects approximately 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 these autoimmune 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 for research on drugs that dissociate the beneficial and detrimental effects of glucocorticoids. The hypothalamic-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 i basic actions of endogenous glucocorticoids

Augmentation of 11β‐hydroxysteroid dehydrogenase type 1 in LPS‐activated J774.1 macrophages – Role of 11β‐HSD1 in pro‐inflammatory properties in macrophages

“…In this context, potential mechanism of LPS-mediated dysfunction of adipose tissue stimulates much interest in future studies. Glucocorticoids are widely used as anti-inflammatory agents in human clinics [23]. Consistent with the notion that glucocorticoids act as anti-inflammatory hormones, our data demonstrated that treatment of J774.1 cells with dexamethasone significantly suppressed the mRNA expression and secretion of IL-1b, TNF-a and MCP-1 in a dose-dependent manner (supplementary figure).…”

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer

“…Glucocorticoids represent one of the most widely used anti-inflammatory drugs (26). Their actions appear to go beyond the anti-inflammatory effects and have been shown to include inhibition of lung cancer cell growth and regulation of cell cycle (27) and chemosensitization of other cytotoxic anti-cancer drugs (28).…”

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

“…In addition, macrophages are central to tissue homeostasis in that they are involved in wound repair and tissue remodeling, secreting critical mediators like TGFβ and metalloproteinases [2,3], The properties of the macrophages are strongly influenced by GC. The effects of GC on immunological functions involves potent antiinflammatory and immunosuppressive properties [4]. The anti-inflammatory effect of GC is mediated through an inhibitory effect on proinflammatory transcription factors such as NF-KB [5], which results in reduced cytokine expression.…”