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Blood, 1 January 2007, Vol. 109, No. 1, pp. 176-184.
Prepublished online as a Blood First Edition Paper on September 7, 2006; DOI 10.1182/blood-2006-01-029199.
 Previous Article | Next Article 
Submitted January 23, 2006
Accepted August 15, 2006
Phospholipase C, calcium and calmodulin are critical for
 4 1 integrin affinity up-regulation and
monocyte arrest triggered by chemoattractants
Sharon J Hyduk, Jason R Chan, Stewart T Duffy, Mian Chen, Mark D Peterson, Thomas K Waddell, Genevieve C Digby, Katalin Szaszi, Andras Kapus, and Myron I Cybulsky*
University of Toronto and University Health Network, Toronto, Ontario, Canada
University Health Network, Toronto, Ontario, Canada
* Corresponding author; email: myron.cybulsky{at}utoronto.ca.
During inflammation, monocytes roll on activated
endothelium and arrest after stimulation by proteoglycan-
bound chemokines and other chemoattractants. We
investigated signaling pathways downstream of G protein-
coupled receptors (GPCR) that are relevant to  4 1 integrin affinity up-regulation using formyl
peptide receptor-transfected U937 cells stimulated with
fMLP or stromal-derived factor-1 and human peripheral
blood monocytes stimulated with multiple chemokines or
chemoattractants. The up-regulation of soluble LDV
peptide or vascular cell adhesion molecule-1 (VCAM-1)
binding by these stimuli was critically dependent on
activation of phospholipase C (PLC), inositol 1,4,5-
triphosphate receptors, increased intracellular calcium,
influx of extracellular calcium and calmodulin,
suggesting that this signaling pathway is required for 4 integrins to assume a high affinity
conformation. In fact, a rise in intracellular calcium
following treatment with thapsigargin or ionomycin was
sufficient to induce binding of ligand. Blockade of
p44/42 and p38 mitogen activated protein (MAP) kinases,
phosphoinositide 3-kinase or protein kinase C (PKC)
signaling did not inhibit chemoattractant-induced LDV or
VCAM-1 binding. However, activation of PKC by phorbol
ester up-regulated 41 affinity with
kinetics distinct from those of GPCR signaling. A
critical role for PLC and calmodulin was also
established for leukocyte arrest and adhesion
strengthening.
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