Corticosteroids can modulate β₂-receptors and their function by several mechanisms:

1. Protection against desensitisation and the development of tolerance
   
   
2. Increased efficiency of receptor coupling
   
   
3. Protection against inflammation-induced receptor down-regulation and uncoupling
   

1. The human β₂-receptor gene has several glucocorticoids response elements (GRE) in its promoter sequence (Fig. 10), thus predicting that corticosteroids should increase transcription.

Figure 10: The effect of corticosteroids on the expression of β₂-receptors. Corticosteroids enter the cell to bind to glucocorticoid receptors in the cytoplasm and then translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) in the promoter region on the β₂-receptor gene, resulting in increased transcription and thus increased synthesis of β₂-receptors.⁷

With regard to this, it has been demonstrated that corticosteroids increase the transcription of β₂-receptor gene in human lung both in vitro and in vivo, doubling the rate of transcription,^9,10 and additional supporting data show that, in normal human subjects, β₂-receptor density in the nasal mucosa is doubled after three days of treatment with intranasal beclomethasone dipropionate (100 μg/day).¹¹ These results have been further confirmed in additional animal studies in which ICSs reversed and, therefore, compensated β₂-receptor down-regulation occurring after chronic exposure to β₂-agonists, so that co-administration of a β₂-agonist and a corticosteroid resulted in no overall change in β₂-receptor expression. This protective effect has been hypothesised not to be so important in terms of effects on airway smooth muscle cells, as the large receptor reserve of β₂-receptors guarantees the bronchodilator response to β₂-agonists not to be desensitised. However, it may be extremely important for the non-bronchodilator actions of β₂-agonists, such as the already described actions on mast cells, plasma exudation and sensory nerves.¹²

2. In one of the studies previously mentioned,¹⁰ corticosteroids resulted to modulate the efficiency of coupling between the β₂-receptor and the associated Gs protein, thus providing an increased β₂-receptor-stimulated adenylate cyclase activity and cAMP accumulation after corticosteroid treatment.

3. Proinflammatory cytokines, such as IL-1β and transforming growth factor (TGF)-β₁, have been demonstrated in animal models to reduce coupling of β₂-receptors to adenylate cyclase; corticosteroids, by reducing the concentration of such cytokines, may prevent or reverse these effects.