Characterization and environmental influences on inflammatory and physiological responses

University dissertation from Örebro : Örebro universitet

Abstract: 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.

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