Corticosteroids as inhibitors of cysteinyl leukotriene metabolic and signaling pathways.
BACKGROUND
Corticosteroids (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).


OBJECTIVE
We 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.


METHODS
We investigated influences of fluticasone on expression of mRNA for LTC(4) synthase (LTC(4)S), 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.


RESULTS
Circulating immune cells (T cells, monocytes, and eosinophils) express low levels of LTC(4)S 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 LTC(4)S 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.


CONCLUSIONS
In 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.
Negri
Julie
J
Asthma and Allergic Disease Center, Beirne Carter Center for Immunology Research, Department of Medicine, University of Virginia Health System, Charlottesville, Va.
Early
S Brandon
SB
Steinke
John W
JW
Borish
Larry
L
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D000730:Androstadienes / Q000494:pharmacology*; D003545:Cysteine / Q000187:drug effects*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D000068298:Fluticasone; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes; D008565:Membrane Proteins / Q000096:biosynthesis / Q000187:drug effects; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000305:Adrenal Cortex Hormones; D000730:Androstadienes; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D015847:Interleukin-4; C412375:cysteinyl leukotriene receptor 2; D000068298:Fluticasone; D003545:Cysteine; C083169:leukotriene D4 receptor