In some cases, glucocorticoids can immediately treat issues with immune activation. This immediate action is not well understood. In animal models, glucocorticoids can stop allergic reactions in five minutes and significantly decrease short term histamine release. Mostly though, glucocorticoids mitigate mast cell activation through delayed actions. This is one of the reasons why premedication with steroids prior to surgery or procedures is recommended to start the day before.
Glucocorticoids affect gene expression, which is one of the reasons they take time to work. Gene expression is very complicated and is highly regulated by cells. Genes are part of your DNA. Think of each gene as a message. When your cell wants to make something using a gene, like a protein, it makes a copy of the message in the gene and then takes it to another part of the cell to make the protein. There are many molecules that affect how easy it is to make something from a gene. Some molecules make it easier and others make it harder. Transcription factors are molecules that sit by genes that make it easier for their message to be made. Interfering with making the message and getting it to the part of the cell where it can make something, like the protein, can drastically alter the behavior of a cell.
One of the major ways that glucocorticoids interfere with making the message is with glucocorticoid receptors. Many people know that receptors are often on the outside of a cell and they are activated when a molecule fits into the receptor like a key into a lock. Glucocorticoid receptors do not work like that. They are small molecules inside cells that are changed when glucocorticoids bind to them.
Cortisol, or other glucocorticoids, bind to the glucocorticoid receptors inside mast cells. When this happens, they interfere with the transcription factors so it is really hard to use the genes. Some of these transcription factors are called NF-kB and AP-1. When glucocorticoid receptors have been activated in the mast cell, the transcription factors can’t help to use the genes.
Cytokines are molecules that cells use to “talk” to each other. Another kind of signal. Glucocorticoids directly interfere with use of cytokine genes so that they aren’t made. Mast cells make many cytokines and they are responsible for a lot of late phase allergic symptoms. Manufacture of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, GM-CSF, TNF and IFN-g (interferon gamma) can all be suppressed with glucocorticoids.
If the cytokine genes have already been used, glucocorticoids can still prevent them from being made. When you use a gene to make something, it creates a messenger RNA (mRNA) that carries the message. If the mRNA falls apart, nothing will be made from the gene. Glucocorticoids make the messages fall apart before making anything for many cytokines, including IL-1, IL-2, IL-6, IL-8, TNF and GM-CSF.
Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.
Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.
Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.
Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.
Sinniah A, et al. The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil. International Immunopharmacology 2016: 32, 87-95.