Inflammation is a crucial biological response to harmful stimuli, including microbial infections and chemical toxins. It involves various immune cells like macrophages, B and T lymphocytes, and endothelial cells, which secrete tumor necrosis factor alpha (TNFα), a key cytokine in the inflammatory process. Dysregulation of TNFα production has been linked to numerous diseases such as inflammatory bowel disease, psoriasis, major depression, Alzheimer's disease, and cancer. The TNFα signaling pathway is therefore a major focus for therapeutic research.
Among the proteins regulated by TNFα is the tumor necrosis factor-α-Induced protein 8 (TNFAIP8/TIPE) family, which includes TNFAIP8, TIPE1, TIPE2, and TIPE3. These proteins share structural similarities but have diverse roles in cellular functions, signaling, and immune responses.
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The TNFAIP8 Family
TNFAIP8 is the first identified member of the TNFAIP8 protein family, which also includes TNFAIP8-like 1 (TIPE1), TNFAIP8-like 2 (TIPE2), and TNFAIP8-like 3 (TIPE3). These proteins share high amino acid sequence homology and a unique structure that includes a death effector domain (DED). The crystal structure of TIPE2 revealed a unique fold among DED-containing proteins. TNFAIP8 and TIPE1 are widely expressed in various tissues, though TIPE1 is absent in mature lymphocytes. TIPE3 is primarily found in non-lymphoid tissues, whereas TIPE2 is localized to immune cells. Down-regulation of TIPE1 is associated with poor cancer prognosis, and it promotes cell death by inhibiting the RAC1 pathway and positively regulates autophagy in Parkinson's disease models. TIPE2 also exhibits antitumor properties and is a key negative regulator of inflammation. TIPE3, recently characterized, promotes tumorigenesis by regulating phosphoinositide signals. All members of the TNFAIP8 family are implicated in tumorigenesis and cell death, highlighting their potential importance in cancer research and treatment.
TNFAIP8 in Cellular Signaling and Cancer
TNFAIP8 plays a critical role in regulating tumor migration, invasion, and angiogenesis, which are key factors in cancer metastasis and recurrence. High levels of TNFAIP8 in tumors inhibit apoptosis and promote cell migration and invasion by modulating the expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor receptor 2 (VEGFR-2). For example, in breast cancer, upregulation of TNFAIP8 increases MMP-1 and MMP-9 expression, enhancing cell migration and invasion. Conversely, reducing TNFAIP8 expression with LE-AS5 leads to decreased VEGFR-2 expression, inhibiting these processes.
Fig. 1 TNFAIP8 through various signaling pathways, ultimately facilitating tumorigenesis and development of tumor (Hua J., et al. 2021).
In various cancers, including esophageal squamous cell carcinoma and osteosarcoma, TNFAIP8 knockdown results in reduced MMP expression and impaired tumor invasiveness. TNFAIP8 also influences cell invasion and migration through interaction with other regulatory proteins such as TAF-Iα and pathways like the Hippo signaling pathway. In lung and hepatocellular cancers, TNFAIP8 inhibits LATS1 and YAP phosphorylation, promoting nuclear localization of YAP and increasing MMP-7 expression.
Additionally, TNFAIP8 affects receptor tyrosine kinase signaling pathways, regulating epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1)-stimulated migration. Knockdown of TNFAIP8 in non-small cell lung cancer cells decreases EGFR levels and increases sensitivity to tyrosine kinase inhibitors. Moreover, TNFAIP8 silencing in colorectal cancer reduces VEGFR-2 expression and angiogenesis through the PI3K-Akt pathway.
Epithelial-mesenchymal transition (EMT), a process driving tumor metastasis, is also regulated by TNFAIP8. In clear cell renal cell carcinoma, high TNFAIP8 expression decreases epithelial markers and increases mesenchymal markers, promoting invasion and migration. Overall, targeting TNFAIP8 holds the potential for developing new cancer therapies by inhibiting tumor growth, migration, and angiogenesis.
TNFAIP8 in Inflammation, Immunity, and Infection
Beyond its role in cancer, TNFAIP8 also modulates inflammatory and immune responses. In macrophages, TNFAIP8 expression is induced by the TLR4 ligand LPS, suggesting its involvement in anti-inflammatory pathways. This regulatory role is further supported by studies showing that TNFAIP8 knockdown leads to increased pro-inflammatory cytokine production.
TNFAIP8's role in bacterial infections has been highlighted in studies on Listeria monocytogenes. TNFAIP8 regulates infection by inhibiting RAC1, a key player in pathogen invasion and host-cell apoptosis. TNFAIP8-knockout mice show resistance to L. monocytogenes, indicating its importance in bacterial immunity. Similarly, TNFAIP8 expression is upregulated in viral infections, promoting cell death in infected cells.
In the immune system, TNFAIP8 is highly expressed in lymphoid tissues and the placenta, suggesting roles in modulating immune responses. Studies in murine models of sepsis show that TNFAIP8 promotes CD4+ T lymphocyte proliferation and polarization, indicating its involvement in T cell-mediated immunity. Moreover, TNFAIP8 facilitates glucocorticoid-induced apoptosis in thymocytes, impacting multiple physiological systems.
Recent research also links TNFAIP8 to acute graft-versus-host disease (GVHD). TNFAIP8 deficiency in allogeneic recipients increases cytokine levels and caspase-3 expression, worsening GI tract pathology. In diabetic nephropathy, TNFAIP8 upregulation in mesangial cells leads to increased cell proliferation and NADPH oxidase-mediated signaling, suggesting its role in kidney disease.
Conclusion and Future Perspectives
TNFAIP8 plays a multifaceted role in oncogenesis, inflammation, immunity, and infection. It is involved in promoting cancer cell survival, proliferation, and resistance to therapy. However, emerging data suggest that TNFAIP8 also modulates inflammatory and immune responses in various disease contexts.
The exact function of TNFAIP8 in chronic inflammatory diseases remains unclear, warranting further investigation. Understanding the roles of different TNFAIP8 variants and their interactions with lipid messengers could reveal new insights into immune regulation. Future research should focus on dissecting these mechanisms to uncover novel therapeutic targets for immune-related diseases.
TNFAIP8 represents a promising area of study, with potential implications for developing new strategies to modulate immune responses and treat various diseases. Its dual role in promoting cancer and regulating inflammation underscores the complexity of its biological functions, highlighting the need for continued exploration of diverse model systems.
References
- Niture S., et al. TNFAIP8: inflammation, immunity and human diseases. Journal of Cellular Immunology. 2019, 1 (2):29.
- Hua J., et al. Current research status of TNFAIP8 in tumours and other inflammatory conditions. International Journal of Oncology. 2021, 59 (1): 1-1.
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