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(Circulation Research. 2005;97:e97.)
© 2005 American Heart Association, Inc.

Research Commentary

Proinflammatory Effects of Bacterial Recombinant Human C-Reactive Protein Are Caused by Contamination With Bacterial Products, Not by C-Reactive Protein Itself

Mark B. Pepys, Philip N. Hawkins, Melvyn C. Kahan, Glenys A. Tennent, J. Ruth Gallimore, David Graham, Caroline A. Sabin, Arturo Zychlinsky, Juana de Diego

From the Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine (M.B.P., P.N.H., M.C.K., G.A.T., J.R.G.), Hampstead Campus, and the Department of Primary Care and Population Sciences (C.A.S.), Royal Free and University College Medical School, London, UK; Scottish National Blood Transfusion Service (D.G.), Pennicuik, Midlothian, Scotland; and the Department of Cellular Microbiology (A.Z., J.d.D.), Max Planck Institute for Infection Biology, Berlin, Germany.

Correspondence to Prof M.B. Pepys FRS, Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom. E-mail m.pepys{at}medsch.ucl.ac.uk

Abstract

Intravenous administration to human volunteers of a commercial preparation of recombinant human C-reactive protein (CRP) produced in Escherichia coli was recently reported in this journal to induce an acute phase response of serum amyloid A protein (SAA) and of CRP itself, and to activate the coagulation system. The authors concluded that CRP is probably a mediator of atherothrombotic disease. Here we confirm that this recombinant CRP preparation was proinflammatory both for mouse macrophages in vitro and for mice in vivo, but show that pure natural human CRP had no such activity. Furthermore mice transgenic for human CRP, and expressing it throughout their lives, maintained normal concentrations of their most sensitive endogenous acute phase reactants, SAA and serum amyloid P component (SAP). The patterns of in vitro cytokine induction and of in vivo acute phase stimulation by the recombinant CRP preparation were consistent with contamination by bacterial products, and there was 46.6 EU of apparent endotoxin activity per mg of CRP in the bacterial product, compared with 0.9 EU per mg of our isolated natural human CRP preparation. The absence of any proinflammatory activity in natural CRP for macrophages or healthy mice strongly suggests that the in vivo effects of the recombinant preparation observed in humans were attributable to proinflammatory bacterial products and not human CRP.

Key Words: C-reactive protein • inflammation • atherosclerosis • atherothrombosis cardiovascular disease

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