Proinflammatory effects of bacterial recombinant human C-reactive protein are caused by contamination with bacterial products, not by C-reactive protein itself.

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.

• Authors: 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
• Journal: Circulation research (Circ Res) Vol. 97 Issue 11 Pg. e97-103 (Nov 25 2005) ISSN: 1524-4571 [Electronic] United States
• PMID: 16254214 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Interleukin-1
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• C-Reactive Protein

Topics

• Acute-Phase Reaction
• Animals
• Atherosclerosis (chemically induced)
• C-Reactive Protein (analysis, toxicity)
• Drug Contamination
• Endotoxins (analysis, toxicity)
• Escherichia coli (genetics, pathogenicity)
• Female
• Humans
• Inflammation (chemically induced)
• Interleukin-1 (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Recombinant Proteins (toxicity)
• Thrombosis (chemically induced)
• Tumor Necrosis Factor-alpha (biosynthesis)