Abstract
The multiple isoforms of p73, a member of the p53 family, share the ability to modulate p53 activities but also have unique properties, leading to a complex and poorly understood functional network. In vivo, p73 isoforms have been implicated in tumor suppression (TAp73−/− mice), DNA damage (ΔNp73−/− mice) and development (p73−/− mice). In this study, we investigated whether TAp73 contributes to innate immunity and septic shock. In response to a lethal lipopolysaccharide (LPS) challenge, TAp73−/− mice showed higher blood levels of proinflammatory cytokines and greater mortality than their wild-type littermates. In vitro, TAp73−/− macrophages exhibited elevated production of tumor necrosis factor alpha , interleukin-6 and macrophage inflammatory protein-2 as well as prolonged survival, decreased phagocytosis and increased major histocompatibility complex class II expression. Mice depleted of endogenous macrophages and reconstituted with TAp73−/− macrophages showed increased sensitivity to LPS challenge. These results suggest that macrophage polarization is altered in the absence of TAp73 such that maintenance of the M1 effector phenotype is prolonged at the expense of the M2 phenotype, thus impairing resolution of the inflammatory response. Our data indicate that TAp73 has a role in macrophage polarization and innate immunity, enhancing the action field of this important regulatory molecule.
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Abbreviations
- LPS:
-
lipopolysaccharide
- TNFα:
-
tumor necrosis factor alpha
- IL:
-
interleukin
- MIP:
-
macrophage inflammatory protein
- MHC:
-
major histocompatibility complex
- TLR:
-
Toll-like receptor
- i.p.:
-
intraperitoneal
- EPM:
-
elicited peritoneal macrophage
- IFN:
-
interferon
- p53RE:
-
p53-responsive element
- CXCL:
-
chemokine
- DC:
-
dendritic cell
- MEF:
-
mouse embryonic fibroblast
- UTR:
-
untranslated region
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Acknowledgements
We thank Dr. Tadatsugu Taniguchi (Department of Immunology, University of Tokyo) for kindly providing the p125 construct containing the IFNβ promoter region, and Dr. Anne Brustle for assistance and helpful discussions. We are grateful to Dr. Mary Saunders for scientific editing. We thank also Jing-Jing Liu for technical assistance. This work was supported by INSERM, and a fellowship award from l’Association pour la recherche contre le cancer (R.T) and Fondation pour la Recherche Medicale (L.P).
Author contributions
RT, GM, TWM and JLI designed the research; RT, VS, LP, AKT, JN and MW performed the research; RT, LP, VS, SV, MW, PB, GM and JLI analyzed the data; and RT wrote the paper.
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Tomasini, R., Secq, V., Pouyet, L. et al. TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses. Cell Death Differ 20, 293–301 (2013). https://doi.org/10.1038/cdd.2012.123
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DOI: https://doi.org/10.1038/cdd.2012.123
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