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Characterization and environmental influences on inflammatory and physiological responses
Örebro University, School of Science and Technology.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmaceuticals are regularly released into the environment, in particular nonsteroidalanti-inflammatory drugs (NSAIDs) and antibiotics. The measuredconcentrations are relatively low and have therefore been considered to be harmless.However, several pharmaceuticals, including naproxen and atenolol, are stable for upto 1 year in the environment, which increases the risk for accumulation. Evaluation ofthe effects of pharmaceuticals on induced inflammatory responses is thereforenecessary for the assessment of potential risks. Since NF-κB and MAPK are the mainpathways known to be critical regulators of inflammatory responses, intracellularsignalling and effects on these systems were examined in vitro using human cell-lines.NSAIDs were shown to significantly reduce NF-κB activity at environmentallyrelevant concentrations. Suppression of immune responses may lead to progressiveinfections since inflammatory responses are controlled by a cooperative activity ofAP-1 and NF-κB. Alterations in the activity of transcription factors and proinflammatorycytokine and chemokine levels such as TNF, IL-6 and CXCL8 areassociated with several human diseases including cystic fibrosis and AIDS. PMAexposure resulted in a rapid NF-κB activation, while extended treatment suppressedNF-κB and activated AP-1. Suppression of NF-κB activity may be due to PKCdependentBcl10 degradation, which decreased in response to PMA and correlatedwith the NF-κB activity. Regulation of cytokine expression revealed that NF-κB wasessential for IL-6 but not CXCL8 expression following specific inhibition of NF-κB,without affecting AP-1 activity. Furthermore, several reports have indicated theimportance of a functional NF-κB complex in zebrafish embryogenesis, whereblockage of NF-κB activation resulted in a deformation of the tail. Our results indicatea suppression of apoptotic pathways following activation of inflammatory mediatorsin response to HK E. coli treatment. These signals acted to direct zebrafish sexdifferentiation towards feminization. NF-κB was shown to regulate zp2 geneexpression, an indicator of oocyte development. Zebrafish sex determination was alsoshown to start early, prior to 16 days post fertilization. The results support thetransition through a juvenile ovary stage and suggests that steriodogenesis is aconsequence of sex differentiation rather than a regulatory mechanism.Control of prescription, use and disposal of pharmaceuticals is therefore importantto preserve human health, biotic processes and to avoid developmental alterations inaquatic organisms. The complexity of regulatory systems involved in inflammationsuggest that there is a need to further evaluate the signalling pathways involved inorder to provide a better understanding of cellular responses to manmade substances,but also to offer an insight into possible development of alternative treatments forhuman diseases with elevated cytokine/chemokine levels.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2010. , p. 53
Series
Örebro Studies in Life Science ; 7
Keywords [en]
Inflammation, NF-κB, cytokines, pharmaceuticals, zebrafish
National Category
Biological Sciences Natural Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-11251ISBN: 978-91-7668-760-4 (print)OAI: oai:DiVA.org:oru-11251DiVA, id: diva2:326944
Public defence
2010-11-19, Hörsal M Musikskolan, Örebro universitet, Fakultetsgatan 1, Örebro, 10:15
Opponent
Supervisors
Note
Note: The article "Involvement of NF-κB and AP-1 in the regulation of IL-6 and CXCL8 in Jurkat T-cells." on page 31 in the disseration is published in BMC Immunology with the new name "Differential cytokine regulation by NF-κB and AP-1 in Jurkat T-cells"Available from: 2010-06-24 Created: 2010-06-24 Last updated: 2017-10-18Bibliographically approved
List of papers
1. Differential cytokine regulation by NF-κB and AP-1 in Jurkat T-cells
Open this publication in new window or tab >>Differential cytokine regulation by NF-κB and AP-1 in Jurkat T-cells
2010 (English)In: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 11, article id 26Article in journal (Refereed) Published
Abstract [en]

Background: Activator protein (AP)-1 and nuclear factor (NF)-κB largely control T-cell activation, following binding offoreign antigens to the T-cell receptor leading to cytokine secretion. Elevated levels of pro-inflammatory cytokines andchemokines such as TNF, IL-6 and CXCL8 are associated with several human diseases including cystic fibrosis, pulmonary fibrosis and AIDS. The aim of this study was to investigate the role of the transcription factors, AP-1 and NF-κB, in IL-6 and CXCL8 regulation in Jurkat T-cells.

Results: Phorbol myristate acetate (PMA) exposure resulted in an up-regulation of AP-1 and down-regulation of NF-κBactivity, however, exposure to heat killed (HK) Escherichia. coli MG1655 resulted in a dose-dependent increase in NF-κBactivity without affecting AP-1. The cytokine profile revealed an up-regulation of the chemokine CXCL8 and the pro-inflammatory cytokines TNF, IL-2 and IL-6 following treatment with both PMA and HK E. coli, while the levels of the anti-inflammatory cytokine IL-10 were not affected by PMA but were significantly down-regulated by HK E. coli. AP-1activation was significantly increased 2 h after PMA exposure and continued to increase thereafter. In contrast, NF-κBresponded to PMA exposure by a rapid up-regulation followed by a subsequent down-regulation. Increased intracellular Ca2+ concentrations countered the down-regulation of NF-κB by PMA, while similar treatment with calcium ionophore resulted in a reduced NF-κB activity following induction with HK E. coli. In order to further study NF-κB activation, we considered two up-stream signalling proteins, PKC and Bcl10. Phosphorylated-PKC levels increased inresponse to PMA and HK E. coli, while Bcl10 levels significantly decreased following PMA treatment. Using an NF-κBactivation inhibitor, we observed complete inhibition of IL-6 expression while CXCL8 levels only decreased by 40% atthe highest concentration. Treatment of Jurkat T-cells with PMA in the presence of JNK-inhibitor suppressed both CXCL8 and IL-6 while PKC-inhibitor primarily decreased CXCL8 expression.

Conclusion: The present study shows that NF-κB regulated IL-6 but not CXCL8. This complex regulation of CXCL8suggests that there is a need to further evaluate the signalling pathways in order to develop new treatment fordiseases with elevated CXCL8 levels, such as AIDS and autoimmune diseases.

Place, publisher, year, edition, pages
London, United Kingdom: BioMed Central, 2010
National Category
Natural Sciences Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-12233 (URN)10.1186/1471-2172-11-26 (DOI)000279893500001 ()20507572 (PubMedID)2-s2.0-77952738203 (Scopus ID)
Available from: 2010-10-18 Created: 2010-10-18 Last updated: 2018-04-19Bibliographically approved
2. Influence of growth conditions on in vitro regulation of NF-κB activity in Jurkat T-cells
Open this publication in new window or tab >>Influence of growth conditions on in vitro regulation of NF-κB activity in Jurkat T-cells
2010 (English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-12234 (URN)
Available from: 2010-10-18 Created: 2010-10-18 Last updated: 2017-10-17Bibliographically approved
3. In vitro analysis of inflammatory responses following environmental exposure to pharmaceuticals and inland waters
Open this publication in new window or tab >>In vitro analysis of inflammatory responses following environmental exposure to pharmaceuticals and inland waters
Show others...
2009 (English)In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 407, no 4, p. 1452-1460Article in journal (Refereed) Published
Abstract [en]

Pharmaceuticals are regularly released into the environment; in particular non-steroidalanti-inflammatory drugs (NSAIDs) and antibiotics. Erythromycin, naproxen, furosemideand atenolol are reported to be stable for up to 1 year in the environment, which increasesthe risk for accumulation. In the present study we have measured the occurrence andconcentration of pharmaceuticals in river Viskan (Jössabron) downstream of a sewagetreatment plant in Borås, Sweden. Pharmaceuticals and water samples were tested forpotential human risk by evaluating inflammatory responses (NF-κB and AP-1) using humanT24 bladder epithelial cells and Jurkat T-cells. NF-κB activity in T24 cells was significantlyreduced by all NSAIDs analysed (diclofenac, ketoprofen, naproxen, ibuprophen anddextropropoxyphene), but also by trimethoprim, using environmentally relevantconcentrations. NF-κB and AP-1 activation was further analysed in response to watersamples collected from different locations in Sweden. Dose-dependent down-regulation ofAP-1 activity in Jurkat cells was observed at all locations. At two locations (Jössabron andAlmenäs) down-regulation of NF-κB was observed. In contrast, the NF-κB response waspotentiated by exposure to water from both locations following activation of NF-κB bytreatment with heat-killed Escherichia coli. To determine the involvement ofpharmaceuticals in the responses, T24 cells were exposed to the pharmaceutical mixture,based on the determined levels at Jössabron. This resulted in reduction of the NF-κBresponse following exposure to the pharmaceutical mixture alone while no potentiationwas observed when cells were co-exposed to heat killed E. coli and pharmaceuticals. Theobtained results demonstrate that the identified pharmaceuticals affect the inflammatoryresponses and furthermore indicate the presence of unknown substance(s) with the abilityto potentiate inflammatory responses

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2009
Keywords
Nuclear factor-κB (NF-κB), Activator protein-1 (AP-1), Pharmaceuticals, Inflammation, Non-steroidal anti-inflammatory drugs
National Category
Natural Sciences Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-12235 (URN)10.1016/j.scitotenv.2008.10.016 (DOI)000262573200022 ()19038416 (PubMedID)2-s2.0-57049179481 (Scopus ID)
Available from: 2010-10-18 Created: 2010-10-18 Last updated: 2017-12-12Bibliographically approved
4. Zebrafish feminization in response to heat killed bacterial exposure suggests a function for anti-apoptotic genes in oocyte maintenance
Open this publication in new window or tab >>Zebrafish feminization in response to heat killed bacterial exposure suggests a function for anti-apoptotic genes in oocyte maintenance
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-12238 (URN)
Available from: 2010-10-18 Created: 2010-10-18 Last updated: 2017-10-17Bibliographically approved

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Khalaf, Hazem

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