Key Takeaways

• The involvement of TNF-alpha in numerous signal transduction pathways links it to diverse functions such as apoptosis, septic shock, acute inflammation, cellular proliferation, and differentiation. Its clinical relevance stems from its association with a myriad of disease states including cancer, Crohn's disease, cachexia, and rheumatoid arthritis.
• Abnormal regulation of VEGF expression has been implicated in a number of neurodegenerative disorders (e.g. motoneuron degeneration).
• There are a number of different strategies to inhibit VEGF cell signaling; they include the development of "humanized neutralizing anti-VEGF monoclonal antibodies, receptor antagonists, soluble receptors, antagonistic VEGF mutants, and inhibitors of VEGF receptor function."

Introduction

GM-CSF

• Granulocyte-macrophage stimulating factor (GM-CSF) is recognized generally as an inflammatory cytokine. GM-CSF assists in the production of white blood cells, macrophages, granulocytes, and the cells that become platelets.
• Its inflammatory activity is primarily due to its "role as a growth and differentiation factor for granulocyte and macrophage populations."
• However, studies found that GM-CSF may also play a role as a regulatory/anti-inflammatory cytokine as well.
•  Elevated levels/production: GM-CSF has been implicated in the inflammatory context, observed in several diseases including rheumatoid arthritis and multiple sclerosis. For example, GM-CSF is found in high levels in joints with rheumatoid arthritis (RA).
•  Reduction/blocking: blocking GM-CSF may reduce damage and/or inflammation. Agents that are able to block GM-CSF (or its corresponding receptor) have been utilized as anti-inflammatory therapies. For example, the inhibition of GM-CSF signaling can be beneficial in the improvement of hyperinflammation-associated lung damage brought on by severe cases of COVID-19.
•  Treatment: natural immunosuppressant compounds that are derived from plant sources such as piperine, resveratrol, luteolin, and curcumin are known to inhibit the production and release of pro-inflammatory cytokines.

SCD40L (Soluble CD40L)

• CD40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) ligand family.
• TNF is a protein in the body; TNF causes inflammation (and helps to coordinate its process). TNF is a "major player when it comes to inflammation." Inflammation is when the immune system, the body's natural defense force is fighting a possible threat.
• High levels of TNF can trigger unpleasant symptoms such as low blood pressure, muscle aches, loss of appetite, redness, swelling (if there is an infected wound), and muscle aches.
• The CD40-CD40L pathway has been discovered to be essential in the mediation of a wide range of immune and inflammatory responses.
• Elevated levels/production: Increased sCD40L levels are associated with inflammatory disorders.
•  Treatment: A study found that ultra-endurance exercise lowers the levels of the sCD40L in athletes.

CCL4 (MIP1beta)

• CCL4 belongs to a family known as chemokines; it is secreted at sites of inflammation.
• MIP1beta attracts a variety of immune cells to "the sites of microbial infection."
• M1P1beta induces the "release of pro-inflammatory cytokines."
•  Elevated levels/production: concentration of CCL4 in the human body increases with age; increased levels are associated with chronic inflammation and liver damage.
•  Reduction/blocking: in mice, CCL4 deficiency promotes the "development of autoantibodies." Another study concluded that decreased MIP1beta levels may be associated with an increased risk of developing nasopharyngeal carcinoma.
•  Treatment: natural immunosuppressant compounds that are derived from plant sources such as piperine, resveratrol, luteolin, and curcumin are known to inhibit the production and release of chemokines.

TNF-alpha

• Human tumor necrosis factor-alpha (TNF-alpha) is a protein that functions as a pro-inflammatory cytokine, Its clinical relevance stems from its association with a myriad of disease states including cancer, Crohn's disease, cachexia, and rheumatoid arthritis.
• The involvement of TNF-alpha in numerous signal transduction pathways links it to diverse functions such as apoptosis, septic shock, acute inflammation, cellular proliferation, and differentiation.
• TNF-Alpha plays a central role in cytokine release syndrome (CRS).
•  Elevated levels/production: Elevated levels of TNF-alpha have been linked to numerous diseases, including, Chrohn's disease, diabetes, and "cachexia associated with AIDS and terminal cancers." Symptoms of high TNF level may include loss of appetite, redness/swelling, low blood pressure, muscle aches, and heavy.
•  Reduction/blocking: Blocking TNF-Alpha may be beneficial for patients with severe inflammation in the lungs due to CRS.
•  Treatment: there are drugs that block excess TNF-alpha called biologics (also called TNF inhibitors, TNF blockers, anti-TNF agents., or anti-TNF drugs); drugs include Adalimumab (Humira, Infliximab (Remicade), and Etanercept (Enbrel). These drugs have been used to treat psoriasis, arthritis, and Crohn's disease. One is also able to reduce TNF levels naturally as well through exercise and adopting an anti-inflammatory diet (e.g. green leafy vegetables, salmon, fruits, and nuts).

VEGF

• VEGF is a signaling protein; it helps to promote the "growth of new blood vessels."
• VEGF inhibits "apoptosis, promotes cell migration, induces endothelial cell proliferation, and induces the permeabilization of blood vessels." The VEGF family consists of the following: VEGF-A (VEGF), VEGF, VEGF-B, VEGF-C, and VEGF-D.
• Abnormal regulation of VEGF expression has been implicated in a number of neurodegenerative disorders (e.g. motoneuron degeneration). The overexpression of VEGF contributes to the development of disease.
•  Elevated level/production: when VEGF is over-expressed, it may contribute to disease. For example, cancers that express VEGF are "able to grow and metastasize."
• Reduction/blocking: according to this study, VEGF is a "critical player in neurodegeneration." Low VEGF levels may cause amyotrophic lateral sclerosis.
•  Treatment: there are a number of different strategies to inhibit VEGF cell signaling; they include the development of "humanized neutralizing anti-VEGF monoclonal antibodies, receptor antagonists, soluble receptors, antagonistic VEGF mutants, and inhibitors of VEGF receptor function." These agents can be divided into two classes: agents designed to "target the VEGF activity and agents designed to target surface receptor function." Drugs that have shown success in slowing the progression of VEGF-reliant diseases include ranibizumab and bevacizumab.

CCL5 (RANTES)

• CCL5, also known as RANTES, plays a primary role in the "inflammatory immune response by means of its ability to attract and activate leukocytes." The CCL5 ligand has been detected in hematological malignancies, lymphomas, and a number of solid tumors.
• CCL5 plays an active role in the recruitment of a number of leukocytes into inflammatory sites including "T-cells, eosinophils, macrophages, and basophils."
•  Elevated levels/production: its production is relevant to inducing "proper immune responses against tumors." Yet, on the other hand, CCL5 is also associated with cancer progression and metastasis.
• Reduction/blocking: according to this study, very low levels of RANTES are associated with mortality.
•  Treatment: it has been documented that physical exercise reduced the expression of RANTES "in the adipose tissue of obese individuals" significantly.

Relationships/Links

GM-CSF — VEGF

• VEGF is a signaling protein that helps to promote the "growth of new blood vessels.
• GM-CSF is prescribed as medication to boost white blood cells following chemotherapy.
• A study reported that GM-CSF upregulates the messenger-RNA and protein production of the soluble form of VEGF receptor-1 in monocytes (white blood cells)

CCL4 — CCL5

• Both CCL4 and CCL5 belong to a family of chemoattractant cytokines known as chemokines.
• Chemoattractant cytokines are small proteins "secreted by cells that influence the immune system."
• Inflammatory chemokines are induced extremely rapidly following tissue insult or infection.

CCL4 — VEGF

• A study found that CCL4 upregulated VEGF-A expression by activating Signal Transducer And Activator Of Transcription 3 (a protein-coding gene).

CCL5 — VEGF

• This study found that CCL5 (RANTES) increased the expression and production of VEGF in human osteosarcoma cells.

VEGF — TNF-alpha

• Studies have shown that TNF-alpha can promote VEGF expression "at the mRNA and protein levels."
• Synergy exists between TNF-alpha and VEGF (e.g. promoting the repair of nerve cells).

sCD40L — TNF-alpha (Decreased levels, Both)

• CD40L is a transmembrane glycoprotein that's structurally related to TNF-alpha.

GM-CSF — TNF

• A study concluded that GM-CSF and TNF act interdependently.

 

Source

Research Strategy