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Phospholipase C, calcium and calmodulin are critical for α4β1 integrin affinity up‐regulation and monocyte arrest triggered by chemoattractants

During inflammation, monocytes roll on activated endothelium and arrest after stimulation by proteoglycan‐bound chemokines and chemoattractants. We investigated signaling pathways downstream of G protein‐coupled receptors (GPCR) that are relevant to α4β1 integrin affinity up‐regulation using formyl peptide receptor‐transfected U937 cells stimulated with fMLP or stromal‐derived factor‐1α and human peripheral blood monocytes stimulated with multiple chemokines or chemoattractants. Affinity up‐regulation, measured by binding of soluble LDV peptide or vascular cell adhesion molecule‐1 (VCAM‐1), was critically dependent on activation of phospholipase C (PLC), inositol 1,4,5‐triphosphate receptors, increased intracellular calcium, influx of extracellular calcium and calmodulin. 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, calpain or protein kinase C (PKC) did not inhibit chemoattractant‐induced LDV or VCAM‐1 binding. However, activation of PKC by phorbol ester increased α4β1 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.