Projects / Programmes
THE ROLE OF CYSTEINE PROTEINASES AND THEIR INHIBITORS IN ENDOTOXIN TOLERANCE
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| 31 |
3000 |
31 |
sepsis, enditoxin tolerance, cysteine proteinases, inhibitors, medications
Researchers (6)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
23573 |
PhD Dejan Caglič |
Biochemistry and molecular biology |
Researcher |
2008 - 2009 |
53 |
| 2. |
18801 |
PhD Marko Fonović |
Biochemistry and molecular biology |
Researcher |
2007 - 2009 |
187 |
| 3. |
25653 |
PhD Špela Konjar |
Chemistry |
Junior researcher |
2007 - 2009 |
59 |
| 4. |
10502 |
PhD Nataša Kopitar Jerala |
Biochemistry and molecular biology |
Head |
2007 - 2009 |
239 |
| 5. |
19366 |
PhD Aleš Premzl |
Pharmacy |
Researcher |
2007 |
81 |
| 6. |
03368 |
PhD Eva Žerovnik |
Biochemistry and molecular biology |
Researcher |
2007 - 2009 |
389 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0106 |
Jožef Stefan Institute |
Ljubljana |
5051606000 |
90,742 |
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”. Induction of tolerance is thought to protect the host from cellular damage caused by hyperactivation of macrophages and other immune cells and likely represents a means of immune cell adaptation to a persistent bacterial infection. The mechanism(s) underlying endotoxin tolerance has not been fully elucidated.
One major feature in both the clinical situation and the in vitro model of endotoxin tolerance is the down-regulation of major histocompatibility complex (MHC) class II surface expression, which is associated with impaired antigen presentation capacity. Endotoxin priming also leads to a reduced expression of the MHC invariant chain and to an inhibited synthesis of the lysosomal enzyme cathepsin S and aspartic endopeptidase (AEP), while the synthesis of cathepsins B and H is up regulated. The gene expression of the intracellular inhibitors of cysteine proteinases stefin B and serpin2A are highly elevated in lipopolysaccharide-stimulated human monocytes. The role of cysteine cathepsins in endotoxin tolerance has already been studied, but the putative interaction with the inhibitors has not been addressed yet. We propose to investigate the interaction of intracellular cysteine proteinase inhibitors with cathepsins in macrophages upon classical activation and induction of endotoxin tolerance and elucidate the role of proteinase – inhibitor interactions as a part of innate immune response to bacterial infection. The elucidation of the role of cysteine proteinase inhibitors in this process may lead not only to the better understanding of the mechanism of endotoxin tolerance, but also to the design and development of new drugs.
Significance for science
The main aim of our research was the understanding of basic mechanisms of activation of macrophages in endotoxin tolerance. The results gave us a new insight into the physiological role of lyososmal cysteine proteinases and inhibitors in this process. We were the first to report that the inhibitors of cysteine proteinases, cystatins and serpins, could regulate the activity of cysteine cathepsins in the nucleus. With FRET method we confirmed the interaction of cathepsin L and stefin B in teh nucleus. The results were relevant also for the medical science, mainly for the understanding of the mechanisms of macrophage activation and inactivation. Increased expression of SpiA3G in the nucleolus and co-localization with cathepsin L, upon classical, but not alternative activation of macrophages, points towards the possible role of this inhibitor in host defense against pathogens.
Significance for the country
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). 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. Knowledge obtained could be translated into strategies for selective immuno modulation for the therapeutic benefit. For the scientific development of Slovenia, collaboration with other research groups in Europe, Australia, China and USA is important. We collaborate only in experiments that could not be performed in Slovenia at the moment.
Most important scientific results
Annual report
2008,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
final report,
complete report on dLib.si
