Inhibition of liver and bone marrow derived dendritic cell maturation and function by Interleukin-6 activation of Signal Transducer and Activator of Transcription-3

Lunz III, John George (2007) Inhibition of liver and bone marrow derived dendritic cell maturation and function by Interleukin-6 activation of Signal Transducer and Activator of Transcription-3. Doctoral Dissertation, University of Pittsburgh.

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Abstract

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.

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