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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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Related in: MedlinePlus

CRP-mediated sIL-6R  production is partially inhibited by  TAPI. Neutrophils (2 × 106 cells) were  pretreated for 10 min with either 100  μM TAPI (black bars) or vehicle alone  (white bars) at 37°C, 5% CO2. Cells  were stimulated for a further 40 min  with 50 μg/ml CRP. Values are representative of three experiments and show  mean sIL-6R production ± SD (n = 3).
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Figure 4: CRP-mediated sIL-6R production is partially inhibited by TAPI. Neutrophils (2 × 106 cells) were pretreated for 10 min with either 100 μM TAPI (black bars) or vehicle alone (white bars) at 37°C, 5% CO2. Cells were stimulated for a further 40 min with 50 μg/ml CRP. Values are representative of three experiments and show mean sIL-6R production ± SD (n = 3).

Mentions: Hydroxamic acid–based metalloprotease inhibitors such as TAPI are known to prevent shedding of various cell surface proteins (25–27), including the IL-6R (12, 20). Surprisingly, the CRP-induced release of sIL-6R by neutrophils was only partially blocked by TAPI (∼20–25%; Fig. 4). Consistent with previous reports (12, 20), TAPI inhibited 70– 75% of the phorbol ester–stimulated sIL-6R production by monocytic THP-1 cells (data not shown). Thus, the mechanism responsible for CRP-induced release of the cognate IL-6R from human neutrophils may be distinct from that described for monocytic cells.


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)

CRP-mediated sIL-6R  production is partially inhibited by  TAPI. Neutrophils (2 × 106 cells) were  pretreated for 10 min with either 100  μM TAPI (black bars) or vehicle alone  (white bars) at 37°C, 5% CO2. Cells  were stimulated for a further 40 min  with 50 μg/ml CRP. Values are representative of three experiments and show  mean sIL-6R production ± SD (n = 3).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2192917&req=5

Figure 4: CRP-mediated sIL-6R production is partially inhibited by TAPI. Neutrophils (2 × 106 cells) were pretreated for 10 min with either 100 μM TAPI (black bars) or vehicle alone (white bars) at 37°C, 5% CO2. Cells were stimulated for a further 40 min with 50 μg/ml CRP. Values are representative of three experiments and show mean sIL-6R production ± SD (n = 3).
Mentions: Hydroxamic acid–based metalloprotease inhibitors such as TAPI are known to prevent shedding of various cell surface proteins (25–27), including the IL-6R (12, 20). Surprisingly, the CRP-induced release of sIL-6R by neutrophils was only partially blocked by TAPI (∼20–25%; Fig. 4). Consistent with previous reports (12, 20), TAPI inhibited 70– 75% of the phorbol ester–stimulated sIL-6R production by monocytic THP-1 cells (data not shown). Thus, the mechanism responsible for CRP-induced release of the cognate IL-6R from human neutrophils may be distinct from that described for monocytic cells.

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