STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells.

@article{citeulike:1390076, abstract = {Interleukin-10-deficient (IL-10(-/-)) mice develop an IL-12-mediated intestinal inflammation in the absence of endogenous IL-10. The molecular mechanisms of the dysregulated IL-12 responses in IL-10(-/-) mice are poorly understood. In this study, we investigated the role of nuclear factor-kappa B (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3) in lipopolysaccharide (LPS)-induced IL-12p40 gene expression in bone marrow derived-dendritic cells (BMDCs) isolated from wild-type (WT) and IL-10(-/-) mice. We report higher IL-12p40 mRNA accumulation and protein secretion in LPS-stimulated BMDCs isolated from IL-10(-/-) compared with WT mice. LPS-induced NF-kappaB signaling is similar in IL-10(-/-) and WT BMDCs as measured by IkappaBalpha phosphorylation and degradation, RelA phosphorylation and nuclear translocation, and NF-kappaB transcriptional activity, with no down-regulatory effects of exogenous IL-10. Chromatin immunoprecipitation demonstrated enhanced NF-kappaB (cRel, RelA) binding to the IL-12p40 promoter in IL-10(-/-) but not WT BMDCs. Interestingly, LPS induced STAT3 phosphorylation in WT but not IL-10(-/-) BMDCs, a process blocked by IL-10 receptor blocking antibody. Adenoviral gene delivery of a constitutively active STAT3 but not control green fluorescence protein (GFP) virus blocked LPS-induced IL-12p40 gene expression and cRel recruitment to the IL-12p40 promoter. In conclusion, dysregulated LPS-induced IL-12p40 gene expression in IL-10(-/-) mice is due to enhanced NF-kappaB recruitment to the IL-12p40 promoter in the absence of activated STAT3.}, address = {Center for Gastrointestinal Biology and Diseases, University of North Carolina at Chapel Hill, USA.}, author = {Hoentjen, F. and Sartor, R. B. and Ozaki, M. and Jobin, C. }, citeulike-article-id = {1390076}, doi = {10.1182/blood-2004-04-1309}, issn = {0006-4971}, journal = {Blood}, keywords = {il-12-general}, month = {January}, number = {2}, pages = {689--696}, posted-at = {2007-06-14 15:28:22}, priority = {2}, title = {STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells.}, url = {http://dx.doi.org/10.1182/blood-2004-04-1309}, volume = {105}, year = {2005} }

TY - JOUR ID - citeulike:1390076 L3 - citeulike-article-id:1390076 TI - STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. JF - Blood VL - 105 IS - 2 SP - 689 EP - 696 AD - Center for Gastrointestinal Biology and Diseases, University of North Carolina at Chapel Hill, USA. SN - 0006-4971 N2 - Interleukin-10-deficient (IL-10(-/-)) mice develop an IL-12-mediated intestinal inflammation in the absence of endogenous IL-10. The molecular mechanisms of the dysregulated IL-12 responses in IL-10(-/-) mice are poorly understood. In this study, we investigated the role of nuclear factor-kappa B (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3) in lipopolysaccharide (LPS)-induced IL-12p40 gene expression in bone marrow derived-dendritic cells (BMDCs) isolated from wild-type (WT) and IL-10(-/-) mice. We report higher IL-12p40 mRNA accumulation and protein secretion in LPS-stimulated BMDCs isolated from IL-10(-/-) compared with WT mice. LPS-induced NF-kappaB signaling is similar in IL-10(-/-) and WT BMDCs as measured by IkappaBalpha phosphorylation and degradation, RelA phosphorylation and nuclear translocation, and NF-kappaB transcriptional activity, with no down-regulatory effects of exogenous IL-10. Chromatin immunoprecipitation demonstrated enhanced NF-kappaB (cRel, RelA) binding to the IL-12p40 promoter in IL-10(-/-) but not WT BMDCs. Interestingly, LPS induced STAT3 phosphorylation in WT but not IL-10(-/-) BMDCs, a process blocked by IL-10 receptor blocking antibody. Adenoviral gene delivery of a constitutively active STAT3 but not control green fluorescence protein (GFP) virus blocked LPS-induced IL-12p40 gene expression and cRel recruitment to the IL-12p40 promoter. In conclusion, dysregulated LPS-induced IL-12p40 gene expression in IL-10(-/-) mice is due to enhanced NF-kappaB recruitment to the IL-12p40 promoter in the absence of activated STAT3. KW - il-12-general AU - Hoentjen, F AU - Sartor, RB AU - Ozaki, M AU - Jobin, C PY - 2005/01/15/ UR - http://dx.doi.org/10.1182/blood-2004-04-1309 ER -