| 1. |
|
|
| 2. |
- Bengtson, Sara, et al.
(författare)
-
Activation of TAFI on the Surface of Streptococcus pyogenes Evokes Inflammatory Reactions by Modulating the Kallikrein/Kinin System
- 2009
-
Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 1:1, s. 18-28
-
Tidskriftsartikel (refereegranskat)abstract
- Bacteria-controlled regulation of host responses to infection is an important virulence mechanism that has been demonstrated to contribute to disease progression. Here we report that the human pathogen Streptococcus pyogenes employs the procarboxypeptidase TAR (thrombin-activatablefibrinolysis inhibitor) to modulate the kallikrein/kinin system. To this end, bacteria initiate a chain of events starting with the recruitment and activation of TAFI. This is followed by the assembly and induction of the contact system at the streptococcal surface, eventually triggering the release of bradykinin (BK). BK is then carboxyterminally truncated by activated TAFI, which converts the peptide from a kinin B-2 receptor ligand to a kinin B-1 receptor (B1R) agonist. Finally, we show that streptococcal supernatants indirectly amplify the B1R response as they act on peripheral blood mononuclear cells to secrete inflammatory cytokines that in turn stimulate upregulation of the B1R on human fibroblasts. Taken together our findings implicate a critical and novel role for streptococci-bound TAR, as it processes BK to a B1R agonist at the bacterial surface and thereby may redirect inflammation from a transient to a chronic state. Copyright (C) 2008 S. Karger AG, Basel
|
|
| 3. |
- Bengtson, Sara H, et al.
(författare)
-
Kinin receptor expression during Staphylococcus aureus infection.
- 2006
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:6, s. 2055-2063
-
Tidskriftsartikel (refereegranskat)abstract
- An inappropriate host response to invading bacteria is a critical parameter that often aggravates the outcome of an infection. Staphylococcus aureus is a major human Gram-positive pathogen that causes a wide array of community- and hospital-acquired diseases ranging from superficial skin infections to severe conditions such as staphylococcal toxic shock. Here we find that S aureus induces inflammatory reactions by modulating the expression and response of the B1 and B2 receptors, respectively. This process is initiated by a chain of events, involving staphylococcal-induced cytokine release from monocytes, bacteria-triggered contact activation, and conversion of bradykinin to its metabolite desArg9bradykinin. The data of the present study implicate an important and previously unknown role for kinin receptor regulation in S aureus infections.
|
|
| 4. |
- Bengtson, Sara
(författare)
-
Inflammation, kinins, and kinin receptors
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Evidence is accumulating that the pathogenesis of many diseases is triggered by inappropriate inflammatory responses. These serious complications may occur when the tightly regulated inflammatory network is out of balance and it is now clear that this can eventually cause substantial harm to own cells and tissues. Successful infectious agents have evolved an enormous repertoire of modulatory mechanisms that allow the evasion, re-direction, dampening, over-stimulation, and even the use of inflammatory responses for their own purposes. The contact system, which is studied in the present thesis, is part of this inflammatory network and it has been shown that its systemic activation contributes to an exacerbation in many disease areas. Bradykinin (BK) belongs to the group of vasoactive peptides, so-called kinins, which are potent inflammatory mediators. BK, once released from the human contact system, elicits a transient inflammatory response via activation of the constitutively expressed B2 receptor, which desensitizes and is internalized upon ligand binding. The kininase I metabolite of BK, desArg9BK, on the other hand mediates chronic deleterious inflammatory responses by interacting with the B1 receptor. Although normally absent, B1 receptor expression can be induced under inflammatory conditions. The aim of the present thesis was to explore and analyze modifications in the regulation of kinins and their receptors in different settings of inflammation. It is known that BK is generated in the airways of asthmatic subjects and that disease symptoms are exacerbated during respiratory viral infections. In paper I, we report that BK induces an up-regulation of B2 receptors in human airway epithelial cells, which is in sharp contrast to other investigated cells. Further more, rhinovirus induces up-regulation of functional B1 receptors in the same cell type (paper II). Both mechanisms may render the respiratory tract more responsive to generated kinins and can significantly influence the inflammatory response and thereby symptom severity. In paper III and IV we demonstrate that the important human pathogens S. aureus and S. pyogenes can induce profound inflammatory reactions in the human host by secreting toxins that via stimulation of monocytic cells induce up-regulation of B1 receptors. Concurrently, both bacterial species are able to induce release of BK and its subsequent conversion to desArg9BK, which can evoke an over-amplification and prolongation of the inflammatory response. Taken together, the present thesis demonstrates that kinin receptor regulation and kinin generation is affected during different settings of inflammation and we conclude that this may have a great impact on disease progression.
|
|
| 5. |
- Bengtson, Sara, et al.
(författare)
-
Regulation of kinin B(2) receptors by bradykinin in human lung cells.
- 2008
-
Ingår i: Biological Chemistry. - 1437-4315. ; 389, s. 1435-1440
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Bradykinin is a potent mediator of inflammation that has been shown to participate in allergic airway inflammation. The biologic effects of bradykinin are mediated by binding and activating its cognate receptor, the B(2) receptor (B(2)R). In the lung fibroblast cell line IMR-90, binding of bradykinin to the B(2)R triggers down-regulation of the receptor surface expression, suggesting that bradykinin-induced inflammation is transient and self-limited. Notably, subjects with chronic airway inflammation continue to respond to BK following a first challenge. B(2)Rs are expressed on many different lung cell types, including airway epithelial cells. We therefore compared IMR-90 cells with the human lung epithelial cell line BEAS2B and found that B2R expression in the two cell types is differently regulated by BK. While BK induces a down-regulation of B(2)R in IMR-90 cells, the same treatment leads to an up-regulation of the receptor in BEAS2B cells. These results provide a possible explanation for the potency of bradykinin in inducing ongoing airway inflammation.
|
|
| 6. |
- Brenden, Nina, et al.
(författare)
-
A triple-transgenic immunotolerant mouse model.
- 2013
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 102:3, s. 1116-24
-
Tidskriftsartikel (refereegranskat)abstract
- Avoiding unwanted immunogenicity is of key importance in the development of therapeutic drug proteins. Animal models are of less predictive value because most of the drug proteins are recognized as foreign proteins. However, different methods have been developed to obtain immunotolerant animal models. So far, the immunotolerant animal models have been developed to assess one protein at a time and are not suitable for the assessment of combination products. Our aim was to develop an animal model for evaluating the impact of manufacturing and formulation changes on immunogenicity, suitable for both single protein and combination products. We constructed two lines of transgenic mice expressing the three human coagulation factors, II, VII, and X, by inserting a single vector containing the three coagulation factors encoding sequences separated by insulator sequences derived from the chicken beta-globin locus into the mouse genome. Immunization of transgenic mice from the two lines and their wild-type littermates showed that transgenic mice from both lines were immunotolerant to the expressed human coagulation factors. We conclude that transgenic mice immunotolerant to multiple proteins can be obtained, and that these mice are potentially useful as animal models in the assessment of immunogenicity in response to manufacturing changes.
|
|
| 7. |
- Ivarsson, Magnus, 1975-, et al.
(författare)
-
Intricate tunnels in garnets from soils and rivere sediments in Thailand - possible endolithic microborings
- 2018
-
Ingår i: PLOS ONE. - Niagara University, USA : Public Library of Science (PLoS). - 1932-6203. ; 13:8
-
Tidskriftsartikel (refereegranskat)abstract
- Garnets from disparate geographical environments and origins such as oxidized soils and river sediments in Thailand host intricate systems of microsized tunnels that significantly decrease the quality and value of the garnets as gems. The origin of such tunneling has previously been attributed to abiotic processes. Here we present physical and chemical remains of endolithic microorganisms within the tunnels and discuss a probable biological origin of the tunnels. Extensive investigations with synchrotron-radiation X-ray tomographic microscopy (SRXTM) reveal morphological indications of biogenicity that further support a euendolithic interpretation. We suggest that the production of the tunnels was initiated by a combination of abiotic and biological processes, and that at later stages biological processes came to dominate. In environments such as river sediments and oxidized soils garnets are among the few remaining sources of bio-available Fe2+, thus it is likely that microbially mediated boring of the garnets has trophic reasons. Whatever the reason for garnet boring, the tunnel system represents a new endolithic habitat in a hard silicate mineral otherwise known to be resistant to abrasion and chemical attack.
|
|
| 8. |
|
|
| 9. |
- Sandén, Caroline, et al.
(författare)
-
Kinin B2 Receptor-Mediated Bradykinin Internalization and Metalloendopeptidase EP24.15-Dependent Intracellular Bradykinin Degradation.
- 2008
-
Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103 .- 0022-3565. ; 326:1, s. 24-32
-
Tidskriftsartikel (refereegranskat)abstract
- Kinins are potent proinflammatory peptides that are produced extracellularly and rapidly degraded by extracellular peptidases and by intracellular peptidases accessed by kinins via receptor-mediated endocytosis. Here, we developed model cell systems expressing the kinin B2 receptor (B2R) and the metalloendopeptidase thimet oligopeptidase (EC 3.4.24.15; EP24.15) either individually or together to address 1) the cellular and functional relationship between these proteins and 2) the participation of EP24.15 in the metabolism of bradykinin (BK) following BK internalization via B2R. B2R was localized almost exclusively in the plasma membrane, whereas EP24.15 was localized both intracellularly and on the cell surface, and secreted in the media. Intracellular EP24.15 was present throughout the cell, both cytosolic and particulate, with less nuclear localization and no co-localization with either the endoplasmatic reticulum marker calnexin or Golgi marker GM130. No direct co-localization of B2R and EP24.15 was observed using immunofluorescence microscopy. However, the two proteins co-immunoprecipitated specifically, and EP24.15 attenuated maximal B2R responsiveness without influencing the potency of BK to stimulate phosphoinositide hydrolysis and intracellular Ca(2+) mobilization. Cell surface-bound BK remained intact in cells overexpressing EP24.15 but was degraded intracellularly in an EP24.15-dependent manner upon B2R-mediated endocytosis. These results show that EP24.15 acts to negatively regulate B2R responsiveness and by serving as an intracellular peptidase in the degradation of BK specifically internalized via this receptor.
|
|
| 10. |
|
|
