Chromatin Binding of c -REL and p65 Is Not Limiting for Macrophage IL12B Transcription During Immediate Suppression by Ovarian Carcinoma Ascites

Frontiers in Immunology
Annika UngerTill Adhikary

Abstract

Tumors frequently exploit homeostatic mechanisms that suppress expression of IL-12, a central mediator of inflammatory and anti-tumor responses. The p40 subunit of the IL-12 heterodimer, encoded by IL12B, is limiting for these functions. Ovarian carcinoma patients frequently produce ascites which exerts immunosuppression by means of soluble factors. The NFκB pathway is necessary for transcription of IL12B, which is not expressed in macrophages freshly isolated from ascites. This raises the possibility that ascites prevents IL12B expression by perturbing NFκB binding to chromatin. Here, we show that ascites-mediated suppression of IL12B induction by LPS plus IFNγ in primary human macrophages is rapid, and that suppression can be reversible after ascites withdrawal. Nuclear translocation of the NFκB transcription factors c-REL and p65 was strongly reduced by ascites. Surprisingly, however, their binding to the IL12B locus and to CXCL10, a second NFκB target gene, was unaltered, and the induction of CXCL10 transcription was not suppressed by ascites. These findings indicate that, despite its reduced nuclear translocation, NFκB function is not generally impaired by ascites, suggesting that ascites-borne signals target additional pa...Continue Reading

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Datasets Mentioned

BETA
GSM1003536
GSM945225
GSM788075
GSM999393

Methods Mentioned

BETA
nuclear translocation
density gradient centrifugation
PCR
RNA-seq
flow cytometry
transfection
FCS
FACS
ELISA
Immunoprecipitation

Key Resources (RRID) Mentioned

AB_571885
AB_2178843
AB_10859369
AB_2134947
AB_2115283
AB_476744
AB_2099233
AB_330924
AB_1163659
AB_1031062

Software Mentioned

Ensembl
MxPro
Image Lab
FACSDiva

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