Thirusha Lane1, Nancy Wassef, Stephen Poole, Yogesh Mistry, Helen J Lachmann, Julian D Gillmore, Philip N Hawkins, Mark B Pepys. 1. From the Wolfson Drug Discovery Unit, and the National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, United Kingdom (M.B.P., T.L., H.J.L., J.D.G., P.N.H.); Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom (N.W.); and the National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom (S.P., Y.M.).
Abstract
RATIONALE: Baseline circulating concentrations of C-reactive protein (CRP) are significantly associated with cardiovascular disease risk in general populations. This modest association has been inappropriately conflated with causality, and it has been claimed that CRP is proatherogenic. Most of the known causative factors for atherosclerosis stimulate increased CRP production, but comprehensive genetic epidemiology studies provide no support for a pathogenic role of CRP. The reported proinflammatory effects of human CRP preparations on healthy cells in vitro and in healthy animals in vivo have all been produced by poorly characterized CRP preparations, demonstrably caused by impurities, or elicited by CRP made in recombinant Escherichia coli not by humans. None of the in vitro or animal findings have been reproduced with pure natural human CRP. Nevertheless, the strong proinflammatory effects of infusing recombinant bacterial CRP into humans have still been inappropriately ascribed to CRP. OBJECTIVE: To investigate the effects of infusion into healthy adult human volunteers of pure natural human CRP. METHODS AND RESULTS: Comprehensively characterized, pharmaceutical-grade, endotoxin-free, purified CRP, prepared to GMP standard from pooled normal human donor plasma was infused as an intravenous bolus in 7 healthy adult human volunteers at ≤2 mg/kg to provide circulating CRP concentrations ≤44 mg/L. No recipient showed any significant clinical, hematologic, coagulation, or biochemical changes, or any increase in proinflammatory cytokines or acute phase proteins. CONCLUSIONS: The human CRP molecule itself is not proinflammatory in healthy human adults.
RATIONALE: Baseline circulating concentrations of C-reactive protein (CRP) are significantly associated with cardiovascular disease risk in general populations. This modest association has been inappropriately conflated with causality, and it has been claimed that CRP is proatherogenic. Most of the known causative factors for atherosclerosis stimulate increased CRP production, but comprehensive genetic epidemiology studies provide no support for a pathogenic role of CRP. The reported proinflammatory effects of human CRP preparations on healthy cells in vitro and in healthy animals in vivo have all been produced by poorly characterized CRP preparations, demonstrably caused by impurities, or elicited by CRP made in recombinant Escherichia coli not by humans. None of the in vitro or animal findings have been reproduced with pure natural human CRP. Nevertheless, the strong proinflammatory effects of infusing recombinant bacterial CRP into humans have still been inappropriately ascribed to CRP. OBJECTIVE: To investigate the effects of infusion into healthy adult human volunteers of pure natural human CRP. METHODS AND RESULTS: Comprehensively characterized, pharmaceutical-grade, endotoxin-free, purified CRP, prepared to GMP standard from pooled normal human donor plasma was infused as an intravenous bolus in 7 healthy adult human volunteers at ≤2 mg/kg to provide circulating CRP concentrations ≤44 mg/L. No recipient showed any significant clinical, hematologic, coagulation, or biochemical changes, or any increase in proinflammatory cytokines or acute phase proteins. CONCLUSIONS: The human CRP molecule itself is not proinflammatory in healthy human adults.
Authors: Birgit Klüppelholz; Barbara Thorand; Wolfgang Koenig; Tonia de Las Heras Gala; Christa Meisinger; Cornelia Huth; Guido Giani; Paul W Franks; Michael Roden; Wolfgang Rathmann; Annette Peters; Christian Herder Journal: Diabetologia Date: 2015-07-09 Impact factor: 10.122
Authors: Jacqueline K Limberg; J Mikhail Kellawan; John W Harrell; Rebecca E Johansson; Marlowe W Eldridge; Lester T Proctor; Joshua J Sebranek; William G Schrage Journal: Am J Physiol Heart Circ Physiol Date: 2014-07-18 Impact factor: 4.733
Authors: Robert Noveck; Erik S G Stroes; JoAnn D Flaim; Brenda F Baker; Steve Hughes; Mark J Graham; Rosanne M Crooke; Paul M Ridker Journal: J Am Heart Assoc Date: 2014-07-10 Impact factor: 5.501