Corticosteroids as inhibitors of cysteinyl leukotriene metabolic and signaling pathways

BackgroundCorticosteroids (CCSs) do not influence secretion of cysteinyl leukotrienes (CysLTs) that occurs on cellular activation during allergic reactions nor do they modulate bronchospastic responses to inhalation challenges with leukotrienes (LTs).ObjectivesWe speculated that CCSs might modulate pathways responsible for CysLT production and diminish the ability of cellular activation to cause their release. Similarly, CCSs could reduce expression of CysLT receptor 1 (CysLTR1) and CysLT receptor 2 (CysLT2R) and modulate their responsiveness.MethodsWe investigated influences of fluticasone on expression of mRNA for LTC4 synthase (LTC4S), CysLT1R, and CysLT2R within T lymphocytes, monocytes, and eosinophils by means of quantitative PCR. Effects on receptor protein expression were evaluated by means of flow cytometry.ResultsCirculating immune cells (T cells, monocytes, and eosinophils) express low levels of LTC4S mRNA, and this was not influenced by CCSs. However, IL-4 induced transcripts in T lymphocytes, and this was prevented by fluticasone. Paradoxically, CCSs synergized with IL-4 to increase LTC4S expression in monocytes. Although not influencing basal or IL-4–stimulated CysLT1R expression, fluticasone inhibited basal CysLT2R transcript expression on monocytes and IL-4–induced expression in all 3 cell types.ConclusionsIn addition to not blocking the acute release of CysLTs on cellular activation, CCSs do not diminish the capacity of cells to synthesize these compounds. CCSs do not diminish CysLT1R expression, consistent with their lack of influence on bronchospasm, which is mediated through this receptor.