Cytokines glucocorticoids effects

In addition to inhibiting cytokine synthesis by glucocorticoids, cytokine effects can be prevented by scavenging the cytokine either with neutralizing antibodies or soluble receptors or by blocking the respective cytokine plasma membrane receptors with blocking antibodies or receptor antagonists. 

Melanocortin peptides are potent anti-inflammatory agents displaying beneficial effects in diseases ranging from cardiovascular to arthritis to obesity to name a few. Within an inflammatory context, they have the ability to switch off early production of cytokines and at later stages they increase levels of anti-inflammatory proteins that lead to the resolution of the host inflammatory response potentially restoring homeostasis to the tissue. They could eventually be viewed as an alternative to glucocorticoids, as their mode of action often resembles that seen... 

In the ebb phase, there is increased activity of the sympathetic nervous system and increased plasma levels of adrenaline and glucocorticoids but a decreased level of insulin. This results in mobilisation of glycogen in the liver and triacylglycerol in adipose tissue, so that the levels of two major fuels in the blood, glucose and long-chain fatty acids, are increased. This is, effectively, the stress response to trauma. These changes continue and are extended into the flow phase as the immune cells are activated and secrete the proinflammatory cytokines that further stimulate the mobilisation of fuel stores (Table 18.2). Thus the sequence is trauma increased endocrine hormone levels increased immune response increased levels of cytokines metabolic responses. 

As mentioned previously, glucocorticoids promote apoptosis and reduce survival, differentiation, and proliferation of a number of inflammatory cells. While there is an increase in the number of polymorphonuclear leukocytes in the circulation, corticosteroids cause the involution and atrophy of all lymphoid tissue and decrease the number of circulating lymphocytes. The striking lymphocytopenia is caused in large part by an inhibition of lymphocyte proliferation, although diminished growth with preferential accumulation of cells in the Gi-phase of the cell cycle is followed by cell death. These effects are mainly mediated by alterations in cytokine production and action. 

The most important clinical application of glucocorticoids and their semisynthetic analogs is their anti-inflammatory activity, discovered in 1949 by Hench and co-workers. The profound anti-inflammatory effects of glucocorticoids arise from the combined effects of these steroids on both the cellular and molecular mediators of inflammation these effects are separate from the metabolic effects described above and further indication of the widespread diversity of macromolecules to which steroids can bind. Glucocorticoids suppress inflammation at the cellular level by downregulating the concentration, distribution, and function of leukocytes (white blood cells) that profoundly influence inflammation and response to infection within the body (In this way, steroids help to mediate the overlap between the endocrine systems [chapter 5] and the immune systems [chapter 6]). Glucocorticoids also suppress inflammation at the molecule level by suppressing inflammatory cytokines, chemokines, and other molecular mediators of inflammation. 

Pace TW, Hu F, Miller AH Cytokine-effects on glucocorticoid receptor function Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007 21(1) 9. [PMID 17070667]... 

Glucocorticoids inhibit acquired or cell-mediated immunity. Their effects are mediated via inhibition of genes that code for various cytokines. The cytokines inhibited by glucocorticoids include IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-y. IL-2 inhibition by corticosteroids is the most crucial effect in immunosuppression, which results in the inhibition of T-cell proliferation and activation of cytolytic T cells. Glucocorticoids also slightly affect humoral immunity by inhibiting B-cell clonal expansion and antibody synthesis, and these effects are mediated via their ability to inhibit B cells ability to express IL-2 and IL-2 receptors. 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

Ciclosporin and related substances inhibit the production of cytokines, in particular interleukin-2. In contrast to glucocorticoids, the plethora of accompanying metabolic effects is absent (see p.306 for more details). 

Both CsA and GC enter cells by diffusion and mediate immunosuppressive effects by binding to receptors cyclophilin in the case of CsA, and glucocorticoid receptor (GR) for GC. CsA prevents activation of lymphocytes. In contrast, GC prevent transcription of proinflammatory cytokines. 

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