Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism
Abstract
Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) plays important roles in negatively regulating the activation of immune cells primarily via the phosphoinositide 3-kinase (PI-3K) pathway by catalyzing the PI-3K product PtdIns-3,4,5P3 (phosphatidylinositol-3,4,5-triphosphate) into PtdIns-3,4P2. However, the role of SHIP1 in Toll-like receptor 4 (TLR4)-mediated lipopolysaccharide (LPS) response remains unclear. Here we demonstrate that SHIP1 negatively regulates LPS-induced inflammatory response via both phosphatase activity-dependent and -independent mechanisms in macrophages. SHIP1 becomes tyrosine phosphorylated and up-regulated upon LPS stimulation in RAW264.7 macrophages. SHIP1-specific RNA-interfering and SHIP1 overexpression experiments demonstrate that SHIP1 inhibits LPS-induced tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production by negatively regulating the LPS-induced combination between TLR4 and myeloid differentiation factor 88 (MyD88); activation of Ras (p21(ras) protein), PI-3K, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase (JNK); and degradation of IkappaB-alpha. SHIP1 also significantly inhibits LPS-induced mitogen-activated protein kinase (MAPK) activation in TLR4-reconstitited COS7 cells. Although SHIP1-mediated inhibition of PI-3K is dependent on its phosphatase activity, phosphatase activity-disrupted mutant SHIP1 remains inhibitory to LPS-induced TNF-alpha production. Ne…
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SHIP1 modulates TLR4 signaling in mouse bone marrow-derived dendritic cells and macrophages.
“SHIP1 also has been shown to modulate toll-like receptor 4 (TLR4) signaling, associated with microglial activation and inflammation upon recognizing PAMPs and DAMPs, in mouse bone marrow-derived dendritic cells and macrophages [121].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [121]
In mouse macrophages, overexpression of SHIP1 inhibits LPS-induced TLR4 signaling and subsequent production of TNF-α and IL-6 by negatively regulating the interaction between TLR4 and MyD88.
“In mouse macrophages, the overexpression of SHIP1 was found to inhibit the LPS-induced TLR4 signaling and the subsequent production of the pro-inflammatory cytokines TNF-α and IL-6 by negatively regulating the interaction between TLR4 and MyD88, though whether this regulation is dependent on SHIP1’s phosphatase activity remains unclear [121, 128]”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [121]
SHIP1 negatively regulates microglia and macrophage phagocytosis, likely through its proposed regulation of TREM2, TLR4, FCγR and CR3-mediated signaling, and potentially other signaling pathways.
“Multiple studies support the hypothesis that SHIP1 negatively regulates microglia and macrophage phagocytosis, likely through its proposed regulation of TREM2 and TLR4, as well as Fc gamma receptor (FCγR) and complement receptor 3 (CR3)-mediated signaling, and potentially of other signaling pathways [106, 114, 121, 134–138].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [121]
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- Authors
- An, H., Xu, H., Zhang, M., Zhou, J., Feng, T., Qian, C., Qi, R., & Cao, X.
- Affiliations
- Second Military Medical University (CN)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2005-06-15
- Volume
- 105
- Issue
- 12
- Pages
- 4685-4692
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2037678644
- Cited by
- 140
- References
- 3
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 10 · 2022: 2 · 2021: 3 · 2020: 9 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 9 · 2012: 9
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- SHIP1, inositol polyphosphate 5-phosphatase, TLR4, lipopolysaccharide, MyD88, macrophages, MAPK signaling, ERK1/2, p38 MAPK, JNK, TNF-α, interleukin-6, phosphatase activity, IκBα degradation
- MeSH terms
- NF-KappaB Inhibitor alpha, Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Wortmannin, Androstadienes, Animals, Antigens, Differentiation, Chromones, Densitometry, Enzyme Activation, Inflammation, Lipopolysaccharides, Luciferases, Macrophages, Morpholines, Phosphoric Monoester Hydrolases, Plasmids, Receptors, Immunologic, Time Factors, Tumor Necrosis Factor-alpha, Blotting, Western, Interleukin-6, Gene Expression Regulation, Enzymologic, Proto-Oncogene Proteins p21(ras), Genes, Reporter, Phosphatidylinositol Phosphates, ras Proteins, src Homology Domains, COS Cells, Phosphatidylinositol 3-Kinases, I-kappa B Proteins, RNA Interference, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88
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