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(Circulation Research. 2005;96:1248.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways

A Vicious Cycle of Inflammation and Arterial Calcification?

Imad Nadra, Justin C. Mason, Pandelis Philippidis, Oliver Florey, Cheryl D.W. Smythe, Geraldine M. McCarthy, Robert C. Landis, Dorian O. Haskard

From the British Heart Foundation Cardiovascular Medicine Unit (I.M., J.C.M., P.P., O.F., C.D.W.S., R.C.L., D.O.H.), Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London; and the Department of Clinical Pharmacology (G.M.M.), The Royal College of Surgeons, Dublin. The current address of R.C.L. is the Edmund Cohen Laboratory for Vascular Research, Chronic Disease Research Centre, Tropical Medicine Research Institute, UWI, Barbados, West Indies.

Correspondence to Dr D.O. Haskard, British Heart Foundation Cardiovascular Medicine Unit, Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Rd, London, W12 ONN UK. E-mail d.haskard{at}imperial.ac.uk

Basic calcium phosphate (BCP) crystal deposition underlies the development of arterial calcification. Inflammatory macrophages colocalize with BCP deposits in developing atherosclerotic lesions and in vitro can promote calcification through the release of TNF alpha. Here we have investigated whether BCP crystals can elicit a proinflammatory response from monocyte-macrophages. BCP microcrystals were internalized into vacuoles of human monocyte-derived macrophages in vitro. This was associated with secretion of proinflammatory cytokines (TNF, IL-1ß and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme. The response of macrophages to BCP crystals suggests that pathological calcification is not merely a passive consequence of chronic inflammatory disease but may lead to a positive feed-back loop of calcification and inflammation driving disease progression.

Key Words: atherosclerosis pathophysiology • cell biology • calcification • inflammation • macrophage

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