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J. Exp. Med.,
Volume 189, Number 3, February 1, 1999 599-604
By
From the * Department of Cell Biology and the 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.
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
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