MEKK3 is essential for lipopolysaccharide‐induced interleukin‐6 and granulocyte–macrophage colony‐stimulating factor production in macrophages
Open accessAbstract
Summary: Mitogen‐activated protein/ERK kinase kinase 3 (MEKK3) is a Ser/Thr protein kinase belonging to the MEKK/STE11 subgroup of the MAP3K family. Recently, we found that MEKK3 plays a critical role in interleukin‐1 (IL‐1) receptor and Toll‐like receptor 4 signalling using established primary mouse embryonic fibroblast (MEF) cell lines. However, the function of MEKK3 in immune cells has not been studied because germ‐line MEKK3 knockout mice are embryonically lethal between embryonic days 10 and 11. In this study, we used small interference RNA to the mouse Mekk3 gene to specifically knock down MEKK3 expression in the macrophage line Raw264.7. We found that the lipopolysaccharide‐induced IL‐6 and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) production was dramatically decreased in MEKK3 knockdown cells whereas the tumour necrosis factor‐α and IL‐1β production were not affected. We also observed that the ERK1/2, p38 and JNK MAPK induction in MEKK3 knockdown cells were moderately inhibited within the first 60 min of stimulation, while the ERK and p38 were more severely inhibited after 2–4 hr of stimulation. Degradation of IκBα was also partially blocked in MEKK3 knockdown cells. Notably, the impairment in IL‐6 and GM‐CSF production in the MEKK3 knockdown cells was restored by reintroducing a human Mekk3 cDNA that could not be targeted by mouse Mekk3‐siRNAs. In conclusion, this study showed that MEKK3 is a crucial and specific regulator of the proinflammatory cytokines IL‐6 and GM‐CSF in macrophages and provided a novel method for investigating MEKK3 function in other immune cells.
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Of the 22 genes in the ACE locus, PSMC5 has a top score of 4, while DDX42, MAP3K3, and CD79B each have a score of 3.
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- Authors
- Kim, K., Duramad, O., Qin, X., & Su, B.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Su, Bing
- Venue
- Immunology
- Publisher
- Wiley
- Published
- 2006-12-18
- Volume
- 120
- Issue
- 2
- Pages
- 242-250
- ISSN
- 0019-2805 (ISSN-L)
- 1365-2567
- PMC
- PMC2265862
- OpenAlex
- W2080945816
- Cited by
- 32
- References
- 31
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 4 · 2019: 4 · 2015: 3 · 2014: 3 · 2013: 1 · 2012: 1
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL070225, HL070225)
- National Cancer Institute (CA-16672, P30CA016672)
- National Institute of Allergy and Infectious Diseases (AI 063348, R01AI063348)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- MEKK3, MAP3K, macrophages, lipopolysaccharide, interleukin-6, GM-CSF, inflammatory cytokines, MAPK signaling, ERK1/2, p38 MAPK, JNK, IκBα degradation, TLR4, interleukin-1 receptor, siRNA knockdown, RAW 264.7 macrophages
- MeSH terms
- Animals, Cell Line, Enzyme Activation, Genetic Vectors, Lipopolysaccharides, Macrophages, Transduction, Genetic, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Lentivirus, Granulocyte-Macrophage Colony-Stimulating Factor, Mitogen-Activated Protein Kinases, RNA, Small Interfering, MAP Kinase Kinase Kinase 3, Toll-Like Receptors, Mice, Interleukin-1beta
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