OVERVIEW OF THE TNF SIGNALING PATHWAY

The TNF signaling pathway, (Tumor Necrosis Factor pathway), plays a central role in mediating inflammation and immune responses, influencing processes from cell survival and proliferation to apoptosis. TNF signaling is pivotal in responding to infections, injuries, and immune challenges, often becoming a critical factor in autoimmune and inflammatory diseases.

AnyGenes offers specialized qPCR array products designed to assist researchers in examining gene expression changes within the TNF signaling pathway. These arrays are invaluable for profiling gene expression linked to inflammation, apoptosis, and immune responses, providing insights that aid in understanding the pathway’s role in disease progression and therapeutic intervention.

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Overview of the TNFR1 and TNFR2 signaling pathway. All TNFR1-exclusive signaling mediators are marked red, whereas all TNFR2-exclusive signaling components are shown in blue. All mediators used by both pathways are labeled orange.

SIGNALING MECHANISMS IN THE THF PATHWAY

Activation of NF-kB: The binding of TNF to TNFR1 leads to the formation of a signaling complex that includes TRADD (TNFR-Associated Death Domain) and RIPK1 (Receptor Interacting Protein Kinase 1). This complex activates the IKK (IκB kinase) complex, resulting in the phosphorylation and degradation of IκB proteins. This degradation releases NF-κB dimers (such as p65/p50), allowing them to translocate to the nucleus and initiate transcription of target genes involved in inflammation and cell survival.
MAPK Pathway Activation: TNF signaling also triggers the MAPK pathway, including ERK, JNK, and p38 MAPKs, leading to cellular responses such as proliferation, differentiation, and stress response. This pathway supports tissue repair and cellular responses to stress, though it may also lead to pathological changes in chronic inflammation.
Regulation of Apoptosis and Cell Survival: In cases where cell death is induced, TRADD recruits FADD (Fas-Associated Death Domain) to form a death-inducing signaling complex (DISC). This complex activates caspase-8, which then initiates a cascade leading to apoptosis through the activation of effector caspases like caspase-3.

KEY COMPONENTS OF THE TNF PATHWAY

TNF Receptors (TNFRs): The TNF signaling pathway is initiated by the binding of Tumor Necrosis Factor (TNF) to its receptors, primarily TNFR1 and TNFR2. TNFR1 is widely expressed in various cell types and mediates the majority of TNF's pro-inflammatory effects.
TRADD and TRAF2: Upon receptor activation, the adaptor protein TNF Receptor Associated Death Domain (TRADD) recruits TRAF2 (TNF Receptor Associated Factor 2). This complex is crucial for downstream signaling and activates various pathways, including NF-κB and MAPK.
NF-κB Pathway: The NF-κB pathway is a key effector of TNF signaling, leading to the transcription of pro-inflammatory genes.
Caspase Activation: In contrast to the pro-survival signals, TNF can also activate apoptotic pathways through caspase-8. This leads to programmed cell death, contributing to tissue homeostasis and response to inflammation.
MAPK Pathway: The activation of MAPK (Mitogen-Activated Protein Kinase) pathways, including ERK, JNK, and p38, plays a significant role in mediating the cellular response to TNF, influencing cell proliferation, differentiation, and survival.
Secondary Messengers: Calcium ions and reactive oxygen species (ROS) act as secondary messengers in TNF signaling, modulating various cellular responses.
Feedback Mechanisms: The TNF pathway is tightly regulated by negative feedback loops, including the expression of soluble TNF receptors and decoy receptors that prevent excessive signaling.

THF SIGNALING IN HEALTH AND DISEASES

In health, the TNF signaling pathway plays a vital role in protecting the body against infections and injuries. It helps to regulate the immune response, promote inflammation to fight off pathogens, and remove damaged cells through apoptosis. However, dysregulation of TNF signaling can lead to pathological conditions.

Chronic activation of the TNF signaling pathway is associated with various inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Additionally, excessive TNF signaling has been implicated in cancer, as it can promote tumor growth and survival. Understanding these mechanisms is crucial for developing therapies aimed at modulating TNF activity in disease.

THERAPEUTICS TARGETS WITHIN THE TNF PATHWAY

Given its central role in inflammation and immune response, the TNF signaling pathway is a prime target for therapeutic intervention. Anti-TNF drugs, such as infliximab and adalimumab, are widely used in treating autoimmune diseases like rheumatoid arthritis and Crohn's disease. These drugs work by neutralizing TNF-alpha, thereby reducing inflammation and tissue damage.

Combination therapies that utilize sTNF/TNFR1 antagonists in conjunction with TNFR2 agonists could help rebalance pathologically deregulated TNF signaling, promoting tissue repair. This approach represents a promising and innovative therapeutic strategy for addressing a variety of inflammatory and degenerative diseases.

(1) Fischer R, et al. Selective Targeting of TNF Receptors as a Novel Therapeutic Approach. Front Cell Dev Biol. (2020)26;8:401.

(2) Webster JD, Vucic D. The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front Cell Dev Biol. (2020)21:8:365.

(3) Holbrook J, et al. Tumour necrosis factor signalling in health and disease. F1000Res. (2019)28;8:F1000 Faculty Rev-111.

TNF SIGNALING PATHWAY BIOMARKER LIST

Customize your own signaling pathways (SignArrays®) with the factors of your choice!
Simply download and complete our Personalized SignArrays® information file and send it at contact@anygenes.com to get started on your project.

You can check the biomarker list included in this pathway, see below :

Species : Homo sapiens (human)

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TNF Signaling Pathway	TNF1H1	List infos

Species : Mus musculus (mouse)

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TNF Signaling Pathway	TNF1M1	List infos

Species : Rattus norvegicus (rat)

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TNF Signaling Pathway	*******	List In progress...

Species : Sus Scrofa (Pig)

Signaling Pathways	Product ref	Informations
TNF Signaling Pathway	*******	List In progress...

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