Projects / Programmes
The role of nuclear cystatins in the regulation of interleukin-10 synthesis during endotoxin tolerance
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B500 |
Biomedical sciences |
Immunology, serology, transplantation |
Cystatin; endotoxin tolerance; epigenetic regulation; interleukin 10.
Researchers (4)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
25653 |
PhD Špela Konjar |
Chemistry |
Junior researcher |
2008 - 2009 |
0 |
| 2. |
10502 |
PhD Nataša Kopitar Jerala |
Biochemistry and molecular biology |
Head |
2008 - 2011 |
0 |
| 3. |
21560 |
PhD Urška Repnik |
Microbiology and immunology |
Researcher |
2008 - 2011 |
0 |
| 4. |
03368 |
PhD Eva Žerovnik |
Biochemistry and molecular biology |
Researcher |
2008 - 2011 |
0 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0106 |
Jožef Stefan Institute |
Ljubljana |
5051606000 |
18 |
Abstract
Sepsis, hemorrhagic shock and trauma are associated with a temporary immunodeficiency, which in its most severe form is referred as immunoparalysis and predisposes to often life threatening infections. Lipopolysaccharide (LPS), also known as endotoxin, is a potent inducer of sepsis and inflammation, acts by stimulating immune system cells to produce proinflammatory cytokines. However, a prior exposure to a low level of LPS induces a transient state of cell refractoriness to subsequent LPS exposure, a phenomenon known as "endotoxin tolerance”. Interleukin -10 (IL-10), inhibits the transcription and translation of a variety of inflammatory cytokines, reduces antigen presentation and inhibits T-cell activation. Recently, it has been shown that the endotoxin tolerance is regulated also at the level of epigenetic modifications. After initial LPS stimulation, the histones associated with both tolerizeable (proinflamatory) and non-tolerizeable (anti microbial) genes transiently undergo chemical modifications that promote the expression of their associated genes. On re-stimulation, tolerizeable (T) genes selectively failed to undergo activating histone modifications. The induction of IL-10 was due, at least in part, to the epigenetic modifications, although additional factors (yet unidentified) were also required. Cystatins were reported to stimulate the synthesis of TNF-? and IL-10 in mouse peritoneal macrophages, by yet unknown mechanism. Serial analysis of gene expression (SAGE) in human monocytes showed that LPS treatment causes up-regulation of cystatin F and stefin B (cystatin B), while cystatin C
Significance for science
Excessive expression of inflammatory mediators during invasive infection plays a key role in the pathogenesis of sepsis, while anti inflamatory cytokines could help to resolve inflammatory response. Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Our results will help to understand the fundamental processes of regulation of gene expression in macrophages. Specifically, we showed that stefin B deficiency influence IL-10 expression. Furtheremore it is a key importance to understand the mechanisms of this action. The main goal of the project was to achieve the fundamental knowledge that can be translated into the clinical applications.
Significance for the country
Although the research on the project was essentialy basic, it has also potential use in immunotherapy. Training of young researchers in the research filed will augment the human potential in the country and also increase the visibility of the country internationally. Young researchers, working on the project, were trained in a variety of methods in immunology, biochemistry, molecular and cell biology. Promotion of Slovenian research in the field of immunology and proteolysis - researchers working on the project were invited lecturers at national and international conferences and have publications in the project field in international journals with high impact factor (IF :5)
Most important scientific results
Annual report
2008,
2009,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
2009,
final report,
complete report on dLib.si
