Dendritic cells(DC) are professional antigen presenting cells bridging the innate and adaptive immune systems by detecting pathogen- and- damage associated molecular pattern(PAMP, DAMP) molecules. This triggers maturation and migration to regional lymph nodes where they stimulate T lymphocytes. In tissues normally exposed to relatively high level of PAMP molecules, such as the liver, DC have a higher threshold to stimulation and therefore maintain an immature phenotype under conditions that would stimulate DC at other sites. In these studies we tested the hypothesis that interleukin-6(IL-6)/Signal Transducer and Activation of Transcription-3(STAT3) activity increases the activation/maturation threshold of hepatic and bone marrow(BM) DC towards innate immune signals.
Results show that liver nuclear STAT3 activity is significantly higher than other organs and is IL-6-dependent. Hepatic DC in normal wild-type(IL-6+/+) mice are phenotypically and functionally less mature than DC from IL-6-deficient(IL-6-/-) or STAT3 inhibited IL-6+/+ mice, as determined by surface marker expression, pro-inflammatory cytokine secretion, and allogenic T-cell stimulation. IL-6+/+ liver DC produce IL-6 in response to exposure to PAMPs, but resist maturation compared to IL-6-/- liver DC. Conversely, exogenous IL-6 inhibits LPS-induced IL-6-/- liver DC maturation. Oral antibiotic depletion of commensal gut bacteria in IL-6+/+ mice decreased portal blood endotoxin levels, lowered IL-6/STAT3 activity and significantly increased liver DC maturation.
BM derived IL-6+/+DC with elevated STAT3 activity are also significantly less mature than IL-6-/- BMDC. The reduced maturation was especially pronounced when IL-6+/+ BMDC when cultured in elevated IL-6 conditions. IL-6 neutralization increased BMDC maturation. Blocking STAT3 activity increases maturation in IL-6+/+ BMDC but not in IL-6-/- BMDC, which have low basal STAT3 activity. Compared to IL-6-/- BMDC, IL-6+/+ BMDC significantly resisted maturation in response to low concentrations of the PAMP molecules. At higher concentrations of these same ligands stimulation of both IL-6+/+ and IL-6-/- BMDC induced maturation.
In Conclusion, gut-derived bacterial products, by stimulating hepatic IL-6/STAT3 signaling, inhibit hepatic DC activation/maturation. Elevated IL-6/STAT3 activity raises the threshold needed for DC to translate triggers of innate immunity into adaptive immune responses. Manipulating gut bacteria or IL-6/STAT3 activity may therefore be an effective strategy to alter intra-hepatic immune responses.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-10172007-135236 |
| Date | 07 December 2007 |
| Creators | Lunz III, John George |
| Contributors | Adriana Zeevi, Stephen Strom, Rene Duquesnoy, Michael Lotze, Anthony J Demetris |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-10172007-135236/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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