Glucocorticoids
A. Wesley Burks MD, in Middleton's Allergy: Principles and Practice, 2020
Infections and Relative Glucocorticosteroid Insensitivity
Up to 80% of asthma exacerbations in adults and children are associated with viral infections, particularly rhinovirus (RV).199 These infections are relatively refractory to high doses of ICS or OCS clinically, which correlates with the lack of effect of ICS on the expression of nasal inflammatory mediators.199 Experimental viral challenge is associated with enhanced oxidative and nitrosative stress and the reduction in HDAC2 expression in COPD patients, and it is likely that this is also the case in severe asthma.200
Corticosteroids also have little clinical benefit in bronchiolitis driven by respiratory syncytial virus (RSV). One action of RSV is to prevent GR nuclear translocation in nasopharyngeal aspirates from RSV-infected infants,201 confirming in vivo evidence previously reported in primary human bronchiolar epithelial cells by RV16.202 With RSV infection the mechanism involves competition of the viral nonstructural protein 1 with GR for importin 13 (IPO13) binding,201 whereas NF-κB and AP-1 pathways are associated with prevention of GR nuclear import, presumably because of changes in GR phosphorylation status, with RV16 infection.202
IFN-γ is induced by viral infection, and this is a dominant variable for chronic persistent obstruction in severe asthma.203 Previous studies have demonstrated that Th1 cytokines, such as TNF-α and IFN-γ, promote corticosteroid resistance in adult human ASM.74 This effect is related, in part, to the induction of interferon regulatory factor (IRF), which competes with GR for limit levels of the transcriptional co-regulator glutamate receptor–interacting protein (GRIP)-1.204 This relative steroid responsiveness is also seen in cells from children with steroid-refractory severe asthma and is selective because corticosteroid-induced gene expression is similar to that in cells from steroid responsive asthmatics.205 GR uses multiple mechanisms to suppress inflammatory gene expression, and activation of TLR9 drives inflammatory responses that are suppressed by activated GR. This effect is via a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IL-1R-associated kinase 1 (IRAK1) ubiquitination.206
It is evident that different genes within each cell type have a variable GR responsiveness and this also varies with cell type, which highlights the concept of pleiotropic gene- and cell-specific effects of dexamethasone.116 In A549 epithelial cells, this variable response to dexamethasone may reflect the relative requirement for the transcription factor IRF1 for inflammatory gene induction.207