Abstract
Human airway smooth muscle (HASM) cells release granulocyte macrophage-colony stimulating factor (GM-CSF) and express cyclooxygenase (COX)-2 (resulting in the release of prostaglandin [PG] E2) after stimulation with cytokines. Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cyclic adenosine monophosphate (cAMP), on GM-CSF release by HASM cells. Cells stimulated with a combination of proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released significant amounts of PGE2 (measured by radioimmunoassay) and GM-CSF (measured by enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 inhibitors caused concentration-dependent inhibitions of PGE2 concomitantly with increases in GM-CSF formation. Addition of exogenous PGE2 or the beta2-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cells had no effect on GM-CSF release unless COX activity was first blocked with indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SB 207499 both caused concentration-dependent reductions in GM-CSF production. Thus, when HASM cells are activated with cytokines they release PGE2, which acts as a "braking mechanism" to limit the coproduction of GM-CSF. Moreover, agents that elevate cAMP also reduce GM-CSF formation by these cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
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Adrenergic beta-Agonists / pharmacology
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Adult
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Asthma / metabolism*
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Asthma / therapy
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Cell Survival / drug effects
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Cells, Cultured
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Cyclic AMP / metabolism*
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cyclooxygenase 1
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / metabolism*
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Dinoprostone / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Female
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
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Humans
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Interleukin-1 / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Male
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Membrane Proteins
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Middle Aged
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Muscle, Smooth / cytology
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Muscle, Smooth / drug effects*
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Muscle, Smooth / metabolism*
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Prostaglandin-Endoperoxide Synthases / metabolism
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Trachea / cytology
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Trachea / drug effects
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Trachea / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Adrenergic beta-Agonists
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Enzyme Inhibitors
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Interleukin-1
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Isoenzymes
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Membrane Proteins
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Tumor Necrosis Factor-alpha
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Granulocyte-Macrophage Colony-Stimulating Factor
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Cyclic AMP
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Cyclooxygenase 1
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Cyclooxygenase 2
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PTGS1 protein, human
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Dinoprostone