The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/2/599/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 3, February 1, 1999 599-604

Brief Definitive Reports

C-reactive Protein: A Physiological Activator of Interleukin 6 Receptor Shedding

Simon A. Jones*, Daniela Novick§, Sankichi Horiuchi||, Naoki Yamamoto||, Alexander J. Szalai{ddagger}, and Gerald M. Fuller*

From the * Department of Cell Biology and the {ddagger} Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama 35294; the § Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel; the || Department of Microbiology, Tokyo Medical and Dental University, Tokyo 113, Japan

The soluble interleukin 6 receptor (sIL-6R) circulates at elevated levels in various diseases. This suggests that inflammatory mediators control sIL-6R release. Through examination of human neutrophils, it was found that the acute phase reactant C-reactive protein (CRP) activates a threefold increase in sIL-6R production. Maximal release occurred after 30–60 min exposure to CRP (50 µg/ml), and was mimicked by peptides corresponding to amino acid residues 174– 185 and 201–206 of native CRP. A third peptide fragment (77–82) had no effect. Differential mRNA splicing did not account for the CRP-mediated release of sIL-6R, since this isoform was not detected in conditioned media. Furthermore, stimulation of neutrophils with CRP or with peptides 174–185 or 201–206 promoted a loss of membrane-bound IL-6R, suggesting release by proteolytic shedding. The metalloprotease inhibitor TAPI had only a marginal effect on CRP-mediated sIL-6R release, suggesting that shedding occurs via a mechanism distinct from that previously reported. It well established that IL-6 stimulates the acute phase expression of CRP. Our current findings demonstrate a novel relationship between these two mediators, since CRP may affect IL-6–mediated inflammatory events by enabling formation of the sIL-6R/IL-6 complex.

Key Words: cytokines • interleukin 6 • soluble receptors • acute phase proteins • inflammation

Address correspondence to Gerald M. Fuller, Department of Cell Biology, University of Alabama at Birmingham, Basic Health Science Bldg., 1918 University Blvd., Birmingham, AL 35294. Phone: 205-934-7596; Fax: 205-934-0950; E-mail: gmfuller{at}bmg.bhs.uab.edu

S.A. Jones's present address is School of Biosciences, University of Wales Cardiff, P.O. Box 911, Cardiff, CF1 3US, UK.


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