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C-reactive protein: a physiological activator of interleukin 6 receptor shedding.

Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM - J. Exp. Med. (1999)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
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 micrograms/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.

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Peptides derived from CRP activate sIL-6R production by human neutrophils. Neutrophils (2 × 106 cells) were stimulated for 45 min at 37°C, 5% CO2 with  peptide (77–82)CRP, (174–185)CRP, or  (201–206)CRP. sIL-6R concentrations are  expressed as the mean ± SD (n = 3). Release of sIL-6R in response to 50 μg/ml  CRP was 177.4 ± 6.5 pg/ml.
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Figure 3: Peptides derived from CRP activate sIL-6R production by human neutrophils. Neutrophils (2 × 106 cells) were stimulated for 45 min at 37°C, 5% CO2 with peptide (77–82)CRP, (174–185)CRP, or (201–206)CRP. sIL-6R concentrations are expressed as the mean ± SD (n = 3). Release of sIL-6R in response to 50 μg/ml CRP was 177.4 ± 6.5 pg/ml.

Mentions: Neutrophil stimulation has been shown to activate the cleavage of native CRP into biologically active peptide fragments (22). In particular, peptides corresponding to amino acid residues 77–82, 174–185, and 201–206 profoundly influence neutrophil responses (23, 24). Accordingly, human neutrophils were incubated with each of these peptides and their capacity to augment sIL-6R production was determined. As shown in Fig. 3, (174–185)CRP and (201–206)CRP stimulated sIL-6R production in a dose-dependent manner, whereas peptide (77–82)CRP had little or no effect.


C-reactive protein: a physiological activator of interleukin 6 receptor shedding.

Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM - J. Exp. Med. (1999)

Peptides derived from CRP activate sIL-6R production by human neutrophils. Neutrophils (2 × 106 cells) were stimulated for 45 min at 37°C, 5% CO2 with  peptide (77–82)CRP, (174–185)CRP, or  (201–206)CRP. sIL-6R concentrations are  expressed as the mean ± SD (n = 3). Release of sIL-6R in response to 50 μg/ml  CRP was 177.4 ± 6.5 pg/ml.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192917&req=5

Figure 3: Peptides derived from CRP activate sIL-6R production by human neutrophils. Neutrophils (2 × 106 cells) were stimulated for 45 min at 37°C, 5% CO2 with peptide (77–82)CRP, (174–185)CRP, or (201–206)CRP. sIL-6R concentrations are expressed as the mean ± SD (n = 3). Release of sIL-6R in response to 50 μg/ml CRP was 177.4 ± 6.5 pg/ml.
Mentions: Neutrophil stimulation has been shown to activate the cleavage of native CRP into biologically active peptide fragments (22). In particular, peptides corresponding to amino acid residues 77–82, 174–185, and 201–206 profoundly influence neutrophil responses (23, 24). Accordingly, human neutrophils were incubated with each of these peptides and their capacity to augment sIL-6R production was determined. As shown in Fig. 3, (174–185)CRP and (201–206)CRP stimulated sIL-6R production in a dose-dependent manner, whereas peptide (77–82)CRP had little or no effect.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

ABSTRACT
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 micrograms/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.

Show MeSH
Related in: MedlinePlus