Glucocorticosteroid effects on cytokine production: studies in a glucocorticosteroid resistance model and in allergic airway disease

Abstract: Glucocorticosteroids (GCS) are potent anti-inflammatory drugs, probably due to inhibitory effects on cytokine production. However, a small number of asthma patients seem GCS-resistant. Pro-inflammatory cytokines, such as interleukin-2(IL-2) and IL-4, produced during allergic airway inflammation have been proposed to induce the resistance to GCS. IL-2 and IL-4 also induce GCS resistance in mononuclear blood cells from healthy subjects, providing an interesting model for studies of GCS mechanisms. The present study demonstrates that production of IL-12 and GM-CSF is very sensitive to GCS inhibition, and confirms previous findings that production of various cytokines is sensitive to GCS to varying degrees. Further, the production of the pro-inflammatory and eosinophilopoietic cytokine GM-CSF became resistant to GCS inhibition after IL-2 and/orIL-4 exposure. However, a general GCS resistance of cytokine production was not induced. Whereas GM-CSF production became GCS-resistant, the GCS sensitivity of TNF-alpha, IL-8 and IL-12 production was unchanged. IL-10 protein production, but not IL-10 mRNA production did also become GCS resistant, indicating that IL-2 and IL-4 may induce GCS resistance at the post-transcriptional level. Despite increased allergic airway inflammation during the pollen season no changes in the sensitivity of GM-CSF production to GCS inhibition in blood cells from allergic asthma and rhinitis patients were observed. In conclusion, the pro-inflammatory cytokines IL-2 and IL-4 may reduce the GCS sensitivity of the production of certain cytokines, such as GM-CSF and IL-10, possibly by post-transcriptional mechanisms. However, allergen induced inflammation did not diminish the sensitivity of GM-CSF production to GCS inhibition in blood cells from patients with seasonal allergic asthma and rhinitis. Indeed, GCS therapy is very efficient in the majority of patients with allergic airway inflammation.