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Cystatin C binds serum amyloid A, downregulating its cytokine-generating properties

Bokarewa, Maria ; Abrahamson, Magnus LU ; Levshin, Nikolay ; Egesten, Arne LU ; Grubb, Anders LU orcid ; Dahlberg, Leif LU and Tarkowski, Andrej (2007) In Journal of Rheumatology 34(6). p.1293-1301
Abstract
Objective. To assess the interaction between cystatin C (CysC) and serum amyloid A protein (SAA). Methods. Levels of CysC and SAA and antibodies against these proteins were assessed in the paired blood and synovial fluid (SF) samples of 90 patients with rheumatoid arthritis (RA). Age and sex matched individuals having normal iohexol clearance (n = 90) and SF following joint trauma (n = 40) were used as controls. In vitro experiments included assessment of interaction between CysC and SAA by ELISA and the influence of CysC on SAA functions. Results. A pilot screening for cystatins C, E, and F in blood and SF of patients with RA found CysC to be by far the predominant extracellular cystatin. Circulating CysC levels were significantly lower... (More)
Objective. To assess the interaction between cystatin C (CysC) and serum amyloid A protein (SAA). Methods. Levels of CysC and SAA and antibodies against these proteins were assessed in the paired blood and synovial fluid (SF) samples of 90 patients with rheumatoid arthritis (RA). Age and sex matched individuals having normal iohexol clearance (n = 90) and SF following joint trauma (n = 40) were used as controls. In vitro experiments included assessment of interaction between CysC and SAA by ELISA and the influence of CysC on SAA functions. Results. A pilot screening for cystatins C, E, and F in blood and SF of patients with RA found CysC to be by far the predominant extracellular cystatin. Circulating CysC levels were significantly lower in patients with RA compared to the matched controls (0.81 +/- 0.03 vs 1.01 +/- 0.03 mg/l; p = 0.05). These low CysC levels could not be explained by the presence of anti-CysC antibodies in patients with RA. In contrast, concentrations of CysC that accumulated in the inflamed SF were significantly greater in patients with erosive RA (1.66 +/- 0.08 mg/l) compared to nonerosive RA (1.36 +/- 0.06 mg/l; p = 0.003) and controls (1.18 +/- 0.03 mg/l; p = 0.043). In vitro studies showed direct binding of CysC to SAA. CysC/SAA binding impaired proinflammatory effects of SAA, reducing its ability to trigger expression of proinflammatory cytokines. Conclusion. Our study shows a relative deficiency of circulating CysC during systemic inflammation in RA. Physical interaction between CysC and the acute-phase protein SAA (1) provides an explanation for CysC deficiency; and (2) suggests that CysC is regulating inflammatory responses. We hypothesize that decreased systemic CysC levels predispose to accelerated atherosclerosis and development of amyloidosis in patients with RA. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cytokines, cystatin C, serum amyloid A, rheumatoid arthritis
in
Journal of Rheumatology
volume
34
issue
6
pages
1293 - 1301
publisher
Journal of Rheumatology Publishing Company Limited
external identifiers
  • wos:000247116600015
  • scopus:34250197588
ISSN
0315-162X
language
English
LU publication?
yes
id
e863c9e2-ddb5-45e0-a7dd-d9d7b2efcb21 (old id 650752)
alternative location
http://www.jrheum.com/abstracts/abstracts07/1293.html
date added to LUP
2016-04-01 12:25:05
date last changed
2023-01-03 08:13:35
@article{e863c9e2-ddb5-45e0-a7dd-d9d7b2efcb21,
  abstract     = {{Objective. To assess the interaction between cystatin C (CysC) and serum amyloid A protein (SAA). Methods. Levels of CysC and SAA and antibodies against these proteins were assessed in the paired blood and synovial fluid (SF) samples of 90 patients with rheumatoid arthritis (RA). Age and sex matched individuals having normal iohexol clearance (n = 90) and SF following joint trauma (n = 40) were used as controls. In vitro experiments included assessment of interaction between CysC and SAA by ELISA and the influence of CysC on SAA functions. Results. A pilot screening for cystatins C, E, and F in blood and SF of patients with RA found CysC to be by far the predominant extracellular cystatin. Circulating CysC levels were significantly lower in patients with RA compared to the matched controls (0.81 +/- 0.03 vs 1.01 +/- 0.03 mg/l; p = 0.05). These low CysC levels could not be explained by the presence of anti-CysC antibodies in patients with RA. In contrast, concentrations of CysC that accumulated in the inflamed SF were significantly greater in patients with erosive RA (1.66 +/- 0.08 mg/l) compared to nonerosive RA (1.36 +/- 0.06 mg/l; p = 0.003) and controls (1.18 +/- 0.03 mg/l; p = 0.043). In vitro studies showed direct binding of CysC to SAA. CysC/SAA binding impaired proinflammatory effects of SAA, reducing its ability to trigger expression of proinflammatory cytokines. Conclusion. Our study shows a relative deficiency of circulating CysC during systemic inflammation in RA. Physical interaction between CysC and the acute-phase protein SAA (1) provides an explanation for CysC deficiency; and (2) suggests that CysC is regulating inflammatory responses. We hypothesize that decreased systemic CysC levels predispose to accelerated atherosclerosis and development of amyloidosis in patients with RA.}},
  author       = {{Bokarewa, Maria and Abrahamson, Magnus and Levshin, Nikolay and Egesten, Arne and Grubb, Anders and Dahlberg, Leif and Tarkowski, Andrej}},
  issn         = {{0315-162X}},
  keywords     = {{cytokines; cystatin C; serum amyloid A; rheumatoid arthritis}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1293--1301}},
  publisher    = {{Journal of Rheumatology Publishing Company Limited}},
  series       = {{Journal of Rheumatology}},
  title        = {{Cystatin C binds serum amyloid A, downregulating its cytokine-generating properties}},
  url          = {{http://www.jrheum.com/abstracts/abstracts07/1293.html}},
  volume       = {{34}},
  year         = {{2007}},
}