Therapeutic immunosuppression
Glucocorticoids cause immunosuppression, and the therapeutic component of this effect is mainly the decreases in the function and numbers of lymphocytes, including both B cells and T cells.
The major mechanism for this immunosuppression through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB). NF-κB is a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote the immune response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response.[2]
Glucocorticoids suppress cell-mediated immunity by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-γ, the most important of which is IL-2. Smaller cytokine production reduces the T cell proliferation.[24]
Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect - glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid sensitivity lies in the Bcl-2 gene.[25]
Glucocorticoids also suppress the humoral immunity, thereby causing a humoral immune deficiency. Glucocorticoids cause B cells to express smaller amounts of IL-2 and of IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated.
The effect of glucocorticoids on Fc receptor expression in immune cells is complicated. Dexamethasone decreases IFN-gamma simulated Fc gamma RI expression in neutrophils while conversely causing an increase in monocytes.[26] Glucocorticoids may also decrease the expression of Fc receptors in macrophages,[27] but the evidence supporting this regulation in earlier studies has been questioned.[28] The effect of Fc receptor expression in macrophages is important since it is necessary for the phagocytosis of opsonised cells. This is because Fc receptors bind antibodies attached to cells targeted for destruction by macrophages.
Anti-inflammatory
Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2),[29] the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.
In addition, glucocorticoids also suppress cyclooxygenase expression
Side effects
Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Side effects include:
Immunodeficiency (see section below)
Hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired glucose tolerance ("steroid diabetes"); caution in those with diabetes mellitus
Increased skin fragility, easy bruising
Negative calcium balance due to reduced intestinal calcium absorption[38]
Steroid-induced osteoporosis: reduced bone density (osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair)
Weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation
Hypercortisolemia with prolonged or excessive use (also known as, exogenous Cushing's syndrome)
Impaired memory and attention deficits[39]
Adrenal insufficiency (if used for long time and stopped suddenly without a taper)
Muscle and tendon breakdown (proteolysis), weakness, reduced muscle mass and repair[40][23]
Expansion of malar fat pads and dilation of small blood vessels in skin
Lipomatosis within the epidural space[41]
Excitatory effect on central nervous system (euphoria, psychosis)
Anovulation, irregularity of menstrual periods
Growth failure, delayed puberty
Increased plasma amino acids, increased urea formation, negative nitrogen balance
Glaucoma due to increased ocular pressure
Cataracts
Topical steroid addiction
In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by rapid degradation of cortisol by 11β-hydroxysteroid dehydrogenase isoenzyme 2 (11β-HSD2) in mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water retention, extracellular fluid volume expansion, hypertension, potassium depletion, and metabolic alkalosis.
Immunodeficiency Edit
Glucocorticoids cause immunosuppression, decreasing the function and/or numbers of neutrophils, lymphocytes (including both B cells and T cells), monocytes, macrophages, and the anatomical barrier function of the skin.[42] This suppression, if large enough, can cause manifestations of immunodeficiency, including T cell deficiency, humoral immune deficiency and neutropenia.
Main pathogens of concern in glucocorticoid-induced immunodeficiency:[42]
Bacteria
Enterobacteriaceae
Legionella micdadei
Listeria monocytogenes
Mycobacterium tuberculosis
Nontuberculous mycobacteria
Nocardia asteroides
Rhodococcus equi
Salmonella species
Staphylococcus aureus
Streptococci
Fungi
Aspergillus
Blastomyces
Candida albicans and nonalbicans species
Coccidioides immitis
Cryptococcus neoformans
Fusarium species
Histoplasma capsulatum
Penicillium marneffei
Pseudallescheria boydii
Zygomycosis
Viruses
Adenovirus
Cytomegalovirus
Herpes simplex virus
Human papillomavirus
Influenza/parainfluenza
Respiratory syncytial virus
Varicella zoster
Other
Cryptosporidiosis/Isospora belli
Pneumocystis carinii
Strongyloides stercoralis
Toxoplasma gondii
