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The protease inhibitor cystatin C downregulates the release of IL-β and TNF-α in lipopolysaccharide activated monocytes

Thiesen, Susanne LU ; Janciauskiene, Sabina LU ; Sandeep, Salipalli; Jonigk, Danny; Kvist, Peter Helding; Gerwien, Jens Gammeltoft; Håkansson, Katarina LU and Grip, Olof LU (2016) In Journal of Leukocyte Biology 100(4). p.811-822
Abstract

Human cystatin C, a member of the cysteine proteinaseinhibitory family, is produced by all nucleated cells and has important roles in regulating natural immunity. Nematode homologs to human cystatin C have been shown to have anti-inflammatory effects on monocytes and to reduce colitis in mice. In Crohn’s disease, pathogenic activated monocytes help drive inflammatory processes via the release of proinflammatory cytokines and chemokines. In particular, tumor necrosis factora-producing inflammatory monocytes have a central role in the intestinal inflammation in patients with Crohn’s disease. We investigated the potential of human cystatin C to regulate pathogenic activated monocytes and its potential as an Immunomodulator in Crohn’s... (More)

Human cystatin C, a member of the cysteine proteinaseinhibitory family, is produced by all nucleated cells and has important roles in regulating natural immunity. Nematode homologs to human cystatin C have been shown to have anti-inflammatory effects on monocytes and to reduce colitis in mice. In Crohn’s disease, pathogenic activated monocytes help drive inflammatory processes via the release of proinflammatory cytokines and chemokines. In particular, tumor necrosis factora-producing inflammatory monocytes have a central role in the intestinal inflammation in patients with Crohn’s disease. We investigated the potential of human cystatin C to regulate pathogenic activated monocytes and its potential as an Immunomodulator in Crohn’s disease.We found that cystatin C significantly decreased the lipopolysaccharide-stimulated release and expression of interleukin-1b and tumor necrosis factor-α in monocyte and peripheral blood mononuclear cell cultures from healthy donors, whereas interleukin-6 and interleukin-8 levels were unchanged. A similar reduction of interleukin-1b and tumor necrosis factor-α was also seen in peripheral bloodmononuclear cell cultures from patientswith Crohn’s disease, and in particular, tumor necrosis factor-α was reduced in supernatants from lamina propria cell cultures from patients with Crohn’s disease. Further investigation revealed that cystatin C was internalized by monocytes via an active endocytic process, decreased phosphorylation of the mitogen-αctivated protein kinase pathway extracellular signal-regulated kinase-1/2, and altered surface marker expression. The ability of cystatin C to modulate the cytokine expression of monocytes, together with its protease-inhibitory function, indicates that modulation of the local cystatin C expression could be an option in future Crohn’s disease therapy.

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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
Crohn’s disease, Cytokines, Immunomodulator, Inflammation, Monocytes
in
Journal of Leukocyte Biology
volume
100
issue
4
pages
12 pages
publisher
Society for Leukocyte Biology
external identifiers
  • scopus:84990057846
  • wos:000382849500019
ISSN
0741-5400
DOI
10.1189/jlb.5A0415-174R
language
English
LU publication?
yes
id
a2ae468b-0a29-4be1-9e39-736f7c6df035
date added to LUP
2016-10-21 12:35:02
date last changed
2017-05-28 04:53:37
@article{a2ae468b-0a29-4be1-9e39-736f7c6df035,
  abstract     = {<p>Human cystatin C, a member of the cysteine proteinaseinhibitory family, is produced by all nucleated cells and has important roles in regulating natural immunity. Nematode homologs to human cystatin C have been shown to have anti-inflammatory effects on monocytes and to reduce colitis in mice. In Crohn’s disease, pathogenic activated monocytes help drive inflammatory processes via the release of proinflammatory cytokines and chemokines. In particular, tumor necrosis factora-producing inflammatory monocytes have a central role in the intestinal inflammation in patients with Crohn’s disease. We investigated the potential of human cystatin C to regulate pathogenic activated monocytes and its potential as an Immunomodulator in Crohn’s disease.We found that cystatin C significantly decreased the lipopolysaccharide-stimulated release and expression of interleukin-1b and tumor necrosis factor-α in monocyte and peripheral blood mononuclear cell cultures from healthy donors, whereas interleukin-6 and interleukin-8 levels were unchanged. A similar reduction of interleukin-1b and tumor necrosis factor-α was also seen in peripheral bloodmononuclear cell cultures from patientswith Crohn’s disease, and in particular, tumor necrosis factor-α was reduced in supernatants from lamina propria cell cultures from patients with Crohn’s disease. Further investigation revealed that cystatin C was internalized by monocytes via an active endocytic process, decreased phosphorylation of the mitogen-αctivated protein kinase pathway extracellular signal-regulated kinase-1/2, and altered surface marker expression. The ability of cystatin C to modulate the cytokine expression of monocytes, together with its protease-inhibitory function, indicates that modulation of the local cystatin C expression could be an option in future Crohn’s disease therapy.</p>},
  author       = {Thiesen, Susanne and Janciauskiene, Sabina and Sandeep, Salipalli and Jonigk, Danny and Kvist, Peter Helding and Gerwien, Jens Gammeltoft and Håkansson, Katarina and Grip, Olof},
  issn         = {0741-5400},
  keyword      = {Crohn’s disease,Cytokines,Immunomodulator,Inflammation,Monocytes},
  language     = {eng},
  month        = {10},
  number       = {4},
  pages        = {811--822},
  publisher    = {Society for Leukocyte Biology},
  series       = {Journal of Leukocyte Biology},
  title        = {The protease inhibitor cystatin C downregulates the release of IL-β and TNF-α in lipopolysaccharide activated monocytes},
  url          = {http://dx.doi.org/10.1189/jlb.5A0415-174R},
  volume       = {100},
  year         = {2016},
}