Am. J. Respir. Cell Mol. Biol., Volume 24, Number 1, January, 2001 44-48

Effects of Prostaglandin E₂ and cAMP Elevating Drugs on GM-CSF Release by Cultured Human Airway Smooth Muscle Cells
Relevance to Asthma Therapy

Nicola Lazzeri, Maria G. Belvisi, Hema J. Patel, Magdi H. Yacoub, K. Fan Chung, and Jane A. Mitchell

Thoracic Medicine and Cardiothoracic Surgery, National Heart and Lung Institute, London; Pharmacology Department, Rhône-Poulenc Rorer Research and Development, Dagenham Research Centre, Dagenham, Essex; and Unit of Critical Care Medicine, Royal Brompton Hospital, Imperial College School of Medicine, London, United Kingdom

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-1 and tumor necrosis factor- 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 ₂-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.

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