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SYNERGISTIC ACTIVATION OF INTERLEUKIN-6 (IL-6) RELEASE BY HUMAN LUNG FIBROBLASTS EXPOSED TO MYCOPLASMA FERMENTANS AND RESIDUAL OIL FLY ASH (ROFA)

Gao, Fei (2006) SYNERGISTIC ACTIVATION OF INTERLEUKIN-6 (IL-6) RELEASE BY HUMAN LUNG FIBROBLASTS EXPOSED TO MYCOPLASMA FERMENTANS AND RESIDUAL OIL FLY ASH (ROFA). Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The adverse health consequences of air pollution are well recognized and range from minor upper respiratory system irritation to severe chronic lung disease. The identity and mechanisms of these pollutants, as well as how toxicity is influenced by additional risk factors are unclear. This study elucidates the relationship between air pollution and microbial agents and explores the mechanisms by which the two stimuli interact to cause adverse health effects with important public health relevance. Mycoplasma fermentans is a species of atypical bacteria with immune-regulatory properties and potential to establish chronic latent infections. Particulate matter (PM) is a complex and diverse component of air pollution associated with adverse health effects. The hypothesis of this study is that M. fermentans infection modulates the cellular responses induced by exposure to residual oil fly ash (ROFA), a type of PM particularly rich in metals. Using human lung fibroblasts (HLF) as an in vitro model I measured the release of the immune-modulating cytokine interleukin-6 (IL-6) as a biomarker of stress-induced cell activation after exposure to various chemical and microbial challenges alone or together. The synergistic interaction between live M. fermentans and ROFA to stimulate IL-6 release and gene expression in HLF was demonstrated. This effect was specific for PM that contains high amounts of water-soluble metal and was recapitulated when NiSO4 was substituted for ROFA. The potentiating effect of live infection was mimicked by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2 agonist. Experiments with consecutive singular exposures to MALP-2 and NiSO4 revealed that pre-treatment of cells with NiSO4 facilitated MALP-2-induced IL-6 production, while pre-exposure to MALP-2 failed to influence the response to Ni. Facilitation of MALP-2 response by NiSO4 depended, in part, upon Ni-induced activation of the ERK1/2 MAP kinase. These interactive effects were studied at the level of gene transcription using a series of IL-6 promoter-luciferase reporter constructs and mutants.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gao, Feifeg2@pitt.eduFEG2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFabisiak, James Pfabs@pitt.eduFABS
Committee CoChairPitt, Bruce Rbrucep@pitt.eduBRUCEP
Committee MemberStripp, Barry Rbrs2@pitt.eduBRS2
Committee MemberTakimoto, Koichikoichi@pitt.eduKOICHI
Committee MemberBarratt Boyes, Simon Msmbb@pitt.eduSMBB
Date: 6 February 2006
Date Type: Completion
Defense Date: 2 September 2005
Approval Date: 6 February 2006
Submission Date: 15 November 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: M. fermentans; MALP-2; MAPK; ROFA; lung fibroblast; Toll-like receptors
Other ID: http://etd.library.pitt.edu/ETD/available/etd-11152005-130323/, etd-11152005-130323
Date Deposited: 10 Nov 2011 20:04
Last Modified: 15 Nov 2016 13:51
URI: http://d-scholarship.pitt.edu/id/eprint/9677

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