PT - JOURNAL ARTICLE AU - A. Y. Meliton AU - N. M. Muñoz AU - A. Lambertino AU - E. Boetticher AU - J. Learoyd AU - X. Zhu AU - A. R. Leff TI - Phosphodiesterase 4 inhibition of β<sub>2</sub>-integrin adhesion caused by leukotriene B<sub>4</sub> and TNF-α in human neutrophils AID - 10.1183/09031936.06.00028406 DP - 2006 Nov 01 TA - European Respiratory Journal PG - 920--928 VI - 28 IP - 5 4099 - http://erj.ersjournals.com/content/28/5/920.short 4100 - http://erj.ersjournals.com/content/28/5/920.full SO - Eur Respir J2006 Nov 01; 28 AB - Phosphodiesterase (PDE)4 inhibition attenuates neutrophilic inflammation in chronic obstructive pulmonary disease. The objective of the present study was to examine the efficacy and mechanism by which PDE4 inhibition blocks adhesion of β2-integrin to an endothelial counterligand. Neutrophils (polymorphonuclear leukocytes (PMNs)) were isolated from humans receiving no medication. Adhesion was analysed by myeloperoxidase activity. The effects of cilomilast±salmeterol on the following were determined: 1) surface CD11b expression; 2) adhesion; 3) intracellular cyclic adenosine monophosphate (cAMP) concentration; and 4) extracellular signal-regulated kinase (ERK)-1/2-mediated group IVA-phospholipase A2 (gIVA-PLA2) phosphorylation caused by leukotriene (LT)B4 or tumour necrosis factor (TNF)-α activation. Either cilomilast or rolipram±salmeterol caused concentration-related blockade of LTB4-induced adhesion to counterligand, but had no effect on TNF-α-activated PMNs. A comparable increase in intracellular cAMP concentration for PMNs activated with LTB4 and TNF-α was caused by 1 μM cilomilast and 0.1 μM salmeterol. Upregulation of surface CD11b expression and ERK-1/2 phosphorylation were blocked by cilomilast or rolipram±salmeterol for PMNs activated by LTB4, but not for cells stimulated by TNF-α. Cilomilast±salmeterol also blocked gIVA-PLA2 phosphorylation caused by LTB4 but not TNF-α. In conclusion, the current study demonstrates that both leukotriene B4 and tumour necrosis factor-α upregulate cyclic adenosine monophosphate. However, cyclic adenosine monophosphate does not block β2-integrin adhesion caused by tumour necrosis factor-α. It was concluded that tumour necrosis factor-α prevents inhibition of extracellular signal-regulated kinase-1/2-mediated group IVA-phospholipase A2 activation, which is essential for β2-integrin adhesion in polymorphonuclear leukocytes.