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Phosphodiesterase 4 inhibition of ß₂-integrin adhesion caused by leukotriene B₄ and TNF- in human neutrophils

¹ Section of Pulmonary and Critical Care Medicine, Dept of Medicine, and ² Depts of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, The University of Chicago, Chicago, IL, USA.

CORRESPONDENCE: A. R. Leff, Dept of Medicine, MC6076, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. Fax: 1 7737029181. E-mail: aleff{at}medicine.bsd.uchicago.edu

Keywords: Adhesion, inflammation, neutrophils, phosphodiesterase 4

Received: February 24, 2006
Accepted June 13, 2006

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 ß₂-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)- activation.

Either cilomilast or rolipram±salmeterol caused concentration-related blockade of LTB₄-induced adhesion to counterligand, but had no effect on TNF--activated PMNs. A comparable increase in intracellular cAMP concentration for PMNs activated with LTB₄ and TNF- 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-. Cilomilast±salmeterol also blocked gIVA-PLA₂ phosphorylation caused by LTB₄ but not TNF-.

In conclusion, the current study demonstrates that both leukotriene B₄ and tumour necrosis factor- upregulate cyclic adenosine monophosphate. However, cyclic adenosine monophosphate does not block ß₂-integrin adhesion caused by tumour necrosis factor-. It was concluded that tumour necrosis factor- prevents inhibition of extracellular signal-regulated kinase-1/2-mediated group IVA-phospholipase A₂ activation, which is essential for ß₂-integrin adhesion in polymorphonuclear leukocytes.

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