PDE4-inhibition on ₂-integrin Adhesion Caused by LTB₄ and TNF in Human Neutrophils

¹ Section of Pulmonary and Critical Care Medicine, Dept of Medicine
² Section of Pulmonary and Critical Care Medicine, Dept of Medicine; and Depts of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, The University of Chicago, Chicago, Illinois 60637.

^* To whom correspondence should be addressed. E-mail: aleff{at}medicine.bsd.uchicago.edu.

	Abstract

Phosphodiesterase (PDE)4-inhibition attenuates neutrophilic inflammation in chronic obstructive pulmonary disease.

The objective of this study was to examine the efficacy and mechanism by which PDE4-inhibition blocks adhesion of ₂-integrin to endothelial counterligand.

Neutrophils (PMN)s were isolated from humans receiving no medications. Adhesion was analyzed by myeloperoxidase activity. The effects of cilomilast±salmeterol on a) surface CD11b expression, b) adhesion, c) intracellular cAMP concentration, and d) ERK-1/2 mediated group IVA-phospholipase A₂ (gIVA-PLA₂) phosphorylation caused by LTB₄ or TNF activation were determined.

Either cilomilast or rolipram±salmeterol caused concentration-related blockade of LTB₄-induced adhesion to counterligand, but had no effect on TNF-activated PMNs. 1µM cilomilast+0.1µM salmeterol caused comparable increase in intracellular cAMP concentration for PMNs activated with LTB₄ and TNF. Upregulation of surface CD11b expression and ERK-1/2 phosphorylation were blocked by cilomilast or rolipram±salmeterol for PMN activated by LTB₄, but not for cells stimulated by TNF. Cilomilast±salmeterol also blocked gIVA-PLA₂ phosphorylation caused by LTB₄ but not TNF.

We demonstrate that both LTB₄ and TNF upregulate cAMP. However cAMP does not block ₂-integrin adhesion caused by TNF. We conclude that TNF prevents inhibition of gIVA-PLA₂ activation, which is essential for ₂-integrin adhesion in PMN.

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