TNFAIP8 Human
Description
Molecular Structure and Variants
TNFAIP8 contains a TIPE2 homologous (TH) domain with six antiparallel α-helices, forming a hydrophobic cavity that binds lipid messengers like phosphatidylinositol . Key structural features include:
Variant 2 (v2) is upregulated in prostate, lung, and gastric cancers, while v1 is downregulated in most malignancies .
Expression Patterns
TNFAIP8 is widely expressed in immune-related tissues (spleen, thymus, lymph nodes) and epithelial organs (lung, gastrointestinal tract) . Dysregulation occurs in multiple cancers:
TNFAIP8 expression is induced by TNF-α/NF-κB signaling and suppressed by COUP-TFI transcriptional repression .
Apoptosis Regulation
TNFAIP8 inhibits caspase activation by competing with FADD for death receptor interactions, promoting cell survival . In Listeria monocytogenes infection, TNFAIP8 deficiency increases hepatocyte apoptosis and reduces bacterial load via RAC1-GTPase modulation .
Immune Modulation
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Reduces pro-inflammatory cytokines (IL-6, IL-8) in TLR4-stimulated macrophages .
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Enhances tumor-infiltrating CD4+/CD8+ T cell survival in thyroid cancer .
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Regulates intestinal epithelial cell renewal, protecting against colitis .
Cancer Progression
In glioma, TNFAIP8 family members (TNFAIP8, TNFAIP8L1-3) correlate with poor survival and immune infiltration .
Therapeutic Targeting
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siRNA knockdown reduces migration in clear cell renal carcinoma (ccRCC) by reversing EMT markers .
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Anti-TNFAIP8 antibodies inhibit xenograft growth in HCC models .
Future Directions
Product Specs
Q&A
What is the TNFAIP8 family and what are its members?
The TNFAIP8 family consists of four homologous proteins: TNFAIP8 (the founding member), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2), and TNFAIP8L3 (TIPE3). These mammalian proteins share high sequence homology but display distinct biological functions and expression patterns. Despite their similarities, each member appears to play specific roles in cellular processes, with TNFAIP8 and TIPE3 primarily studied in tumorigenesis contexts, while TIPE1 and TIPE2 have been more extensively characterized in immune regulation .
Where is TNFAIP8 expressed in human tissues?
TNFAIP8 transcripts are widely distributed across human tissues, with expression detected in bone marrow, immune cells, adipose tissue, gastrointestinal tract, lung, pancreas, placenta, salivary and thyroid glands, kidney, liver, ovary, and prostate tissues. The expression of TNFAIP8 proteins is notably induced in response to TNFα-mediated cellular inflammation . This widespread expression pattern suggests fundamental cellular roles across diverse tissue types, necessitating tissue-specific research approaches when studying TNFAIP8 functions.
How is TNFAIP8 gene expression regulated?
The regulation of TNFAIP8 involves multiple transcription factors beyond TNFα induction. Key regulatory elements include nuclear factor-κB (NF-κB), androgen receptor (AR), p53, and orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) . When designing experiments to study TNFAIP8 expression, researchers should consider these diverse regulatory influences and potentially incorporate multiple stimuli to fully characterize expression patterns in different cellular contexts.
What are the different isoforms of human TNFAIP8?
The human TNFAIP8 gene encodes eight transcript variants/isoforms, with five protein variants reported to date. Of these, TNFAIP8 variant 2 appears to be predominantly expressed in prostate, breast, liver, and lung cancer cells, as well as in acute monocytic leukemia-derived THP1 cells . Researchers should employ isoform-specific detection methods (such as targeted PCR primers or antibodies) to differentiate between these variants, as their functions may differ substantially.
How does TNFAIP8 contribute to immune regulation and inflammatory responses?
While initially characterized in cancer contexts, emerging evidence indicates that TNFAIP8 plays significant roles in immune regulation. In macrophages stimulated with the TLR4 ligand LPS, TNFAIP8 variants 1 and 2 are induced with different kinetics. Knockdown studies in A549 cells demonstrated that TNFAIP8 variant 2 regulates anti-inflammatory pathways in both resting and TLR ligand-stimulated cells, affecting the expression of pro-inflammatory cytokines (IL-6, IL-8, IL-1β, and TNFα) .
For researchers investigating TNFAIP8's immune functions, it is crucial to:
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Distinguish between different variants/isoforms in experimental designs
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Assess both baseline and stimulated conditions
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Measure multiple downstream inflammatory mediators
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Consider cell type-specific effects, as responses in macrophages, T cells, and other immune cells may differ substantially
What is the relationship between TNFAIP8 expression and immune cell infiltration in tumors?
Advanced analysis of TNFAIP8 expression in glioma reveals significant associations with immune cell infiltration patterns. Compared to tumors with low TNFAIP8 expression, those with high expression show increased enrichment of activated dendritic cells (aDC), B cells, cytotoxic cells, eosinophils, immature dendritic cells (iDC), macrophages, neutrophils, NK CD56dim cells, and various T cell subsets including T helper cells, Th1, Th17, and Th2 cells .
Conversely, CD8 T cells, NK CD56bright cells, plasmacytoid dendritic cells (pDC), central memory T cells (Tcm), T follicular helper cells (TFH), gamma-delta T cells (Tgd), and regulatory T cells (Treg) show lower enrichment in TNFAIP8-high tumors . This complex pattern suggests that TNFAIP8 may influence the tumor immune microenvironment in sophisticated ways, potentially serving as both an immunological biomarker and therapeutic target.
How do genetic alterations in TNFAIP8 affect clinical outcomes in cancer patients?
The specific alteration patterns vary by family member:
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TNFAIP8: primarily missense mutations
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TNFAIP8L1: predominantly amplifications (1.5% frequency) and deep deletions
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TNFAIP8L2: amplification mutations only
These findings suggest that genetic screening of TNFAIP8 family members could provide valuable prognostic information for cancer patients, particularly those with gliomas.
What are the recommended approaches for studying TNFAIP8 isoform-specific functions?
Given that human TNFAIP8 exists in multiple isoforms with potentially distinct functions, isoform-specific experimental approaches are essential. Recommended methodologies include:
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Isoform-specific siRNA/shRNA: Design silencing RNAs that target unique regions of each isoform to selectively knock down individual variants.
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Overexpression systems: Generate expression constructs for each isoform separately, using appropriate tags for detection while ensuring the tags do not interfere with protein function.
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Quantitative PCR: Design primers that span unique exon junctions for each isoform to quantify their relative expression levels across tissues or experimental conditions.
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Western blotting: When possible, use antibodies that can distinguish between isoforms, or combine with isoform-specific expression systems.
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CRISPR-Cas9 gene editing: For more definitive functional studies, design guide RNAs targeting specific isoforms while leaving others intact .
How should researchers assess the role of TNFAIP8 in inflammation and immune response?
To comprehensively evaluate TNFAIP8's role in inflammation and immunity, researchers should consider the following methodological approaches:
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Stimulation protocols: Use diverse inflammatory stimuli beyond TNFα, including TLR ligands, cytokines, and bacteria/bacterial components to trigger TNFAIP8 expression.
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Time-course analyses: Monitor TNFAIP8 expression and downstream effects over multiple time points, as different isoforms show distinct temporal expression patterns.
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Cell type consideration: Study TNFAIP8 in various immune cell types, including macrophages, T lymphocytes, and dendritic cells, as its functions appear to be cell type-dependent.
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In vivo models: Incorporate models such as cecal ligation and puncture (CLP) in mice to assess TNFAIP8's role in sepsis and immune dysfunction.
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Immune cell phenotyping: Analyze how TNFAIP8 manipulation affects immune cell polarization, proliferation, and effector functions .
How should researchers interpret conflicting data regarding TNFAIP8's role in different cancer types?
TNFAIP8 exhibits context-dependent functions across different cancer types, sometimes yielding seemingly contradictory results. When faced with conflicting data, researchers should:
What statistical approaches are recommended for analyzing TNFAIP8 expression correlations with patient outcomes?
For robust analysis of TNFAIP8's prognostic significance, researchers should employ the following statistical approaches:
What are the most promising areas for future investigation of TNFAIP8 in human disease?
Based on current knowledge gaps, several high-priority research directions emerge:
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Isoform-specific functions: Comprehensive characterization of all eight transcript variants and five protein isoforms of TNFAIP8, focusing on their differential regulation and biological roles.
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Immune regulation mechanisms: Further investigation of how TNFAIP8 modulates specific immune pathways, particularly in chronic inflammatory diseases where its exact function remains unknown.
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Therapeutic targeting: Development of isoform-specific inhibitors or modulators of TNFAIP8 for potential application in cancer and inflammatory conditions.
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Biomarker validation: Validation of TNFAIP8 expression as a prognostic or predictive biomarker across diverse cancer types, including standardization of detection methods.
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Lipid interactions: Exploration of the biological significance of TNFAIP8 complexed with phospholipids or fatty acids in immune response, as this remains poorly understood .
What technologies and methodologies will be most valuable for advancing TNFAIP8 research?
Emerging technologies that could significantly advance TNFAIP8 research include:
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Single-cell RNA sequencing: To elucidate cell type-specific expression patterns and functions of TNFAIP8 isoforms within heterogeneous tissues and tumors.
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Spatial transcriptomics: To map TNFAIP8 expression patterns within the tumor microenvironment and correlate with immune cell localization.
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CRISPR-based screening: For high-throughput identification of genes that interact with TNFAIP8 in different cellular contexts.
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Protein interaction proteomics: To comprehensively characterize TNFAIP8's interactome across different cell types and conditions.
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Patient-derived organoids: To study TNFAIP8 functions in more physiologically relevant models that recapitulate patient-specific contexts .
Product Science Overview
TNFAIP8 was initially identified as a gene induced by tumor necrosis factor-alpha (TNF-α), a cytokine involved in systemic inflammation and a member of a group of cytokines that stimulate the acute phase reaction . The protein consists of a death effector domain (DED), which is a common feature among the TNFAIP8 family members . This domain is crucial for the protein’s role in inhibiting apoptosis.
TNFAIP8 acts as a negative mediator of apoptosis, primarily by inhibiting the activity of caspase-8, an enzyme that plays a key role in the execution-phase of cell apoptosis . By inhibiting caspase-8, TNFAIP8 prevents the cleavage of BID (BH3 interacting-domain death agonist) and the activation of caspase-3, another critical enzyme in the apoptosis pathway . This inhibition results in the suppression of TNF-mediated apoptosis, which can contribute to tumor progression by allowing cancer cells to evade programmed cell death.
The excessive production of TNF-α and the subsequent induction of TNFAIP8 have been implicated in various inflammatory diseases and cancers . For instance, TNFAIP8 expression is upregulated in several types of cancers, including head and neck squamous cell carcinoma, where it is associated with tumor progression and poor prognosis . Additionally, TNFAIP8 has been shown to play a role in immune regulation by negatively regulating T-cell receptor (TCR) and Toll-like receptor (TLR) signal transduction, thereby maintaining immune homeostasis .
Given its role in inhibiting apoptosis and promoting tumor progression, TNFAIP8 is considered a potential therapeutic target for cancer treatment. Inhibiting TNFAIP8 function could restore the apoptotic pathways in cancer cells, making them more susceptible to cell death and reducing tumor growth . Furthermore, targeting TNFAIP8 could also have therapeutic implications for inflammatory diseases where TNF-α plays a critical role .
