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Enhanced LPS-induced peritonitis in mice deficiency of cullin 4B in macrophages

Genes & Immunity volume 15, pages 404–412 (2014)Cite this article

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Abstract

Cullin 4B (CUL4B), a member of the cullin protein family, is a scaffold protein of the CUL4B–RING–E3 ligase complex that ubiquitinates intracellular proteins.CUL4B’s targets include cell cycle-regulated proteins and DNA replication-related molecules. In this study, we generated myeloid-specific Cul4b-deficient mice (Cul4bf/y;LysM-CreKI/KI) to investigate the influence of Cul4b deficiency on innate immunity, especially on the function of macrophages. Our results show that an intraperitoneal injection of lipopolysaccharide (LPS) led to a significant decrease in body weights and increased leukocyte infiltrates with increased chemokines in the peritoneal cavity of Cul4bf/y;LysM-CreKI/KI mice. However, the proinflammatory cytokines, IL-6 and TNF-α did not increase in LPS-injected Cul4bf/y;LysM-CreKI/KI mice. Furthermore, bone marrow-derived macrophages from Cul4bf/y;LysM-CreKI/KI mice secreted higher levels of chemokines but lower levels of TNF-α and IL-6 upon LPS stimulation. Of note, increased proliferation of Cul4b-deficient macrophages was also observed. These results show that myeloid-specific Cul4b deficiency worsens LPS-induced peritonitis. In addition, Cul4b deficiency leads to enhanced DNA replication and proliferation, increased production of chemokines but a decreased production of proinflammatory cytokines of macrophages. Our data highlight a new role of cullin family, CUL4B, in the immune system.

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Acknowledgements

This work was supported by grants from the National Science Council, Taiwan (NSC99-2320-B-002-060-MY3). We thank Dr Chun-Yu Chen for critical reading the manuscript and technical support. We thank the technical services provided by the ‘Transgenic Mouse Model Core Facility of the National Core Facility Program for Biotechnology, National Science Council’ and the ‘Gene Knockout Mouse Core Laboratory of National Taiwan University Center of Genomic Medicine’. We thank the Taiwan Mouse Clinic (NSC 102-2325-B-001-042), which is funded by the National Research Program for Biopharmaceuticals (NRPB) at the National Science Council (NSC) of Taiwan for technical support in CBC experiment.

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  1. Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan

    M-H Hung, Y-R Jian, C-C Tsao, S-W Lin & Y-H Chuang

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  1. M-H Hung
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  2. Y-R Jian
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Correspondence to S-W Lin or Y-H Chuang.

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Hung, MH., Jian, YR., Tsao, CC. et al. Enhanced LPS-induced peritonitis in mice deficiency of cullin 4B in macrophages. Genes Immun 15, 404–412 (2014). https://doi.org/10.1038/gene.2014.32

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