As you know, there are many contributing factors in developing Hepatocellular cancer in hepatitis C patients which some of them are immune mediated factors. TLR4 is one of the immune mediated factors. I'm studying about its role in developing HCC IN HCV patients. I need your experience in this regard or your point of view.
Dear Dr. Sepehri,
According to results of other studies, we could assume some mechanisms for TLR4 and developing HCC:
1. TLR4 signaling is involved in the invasion and metastasis of HCC and suggested that NF-κB may be directly activated by TLR4 signaling pathway.
2. TLR4-dependent signaling enhanced TGF-β signaling pathway.
3. TLR4 may indirectly facilitate the recruitment of regulatory T-cells to the tumor site and promote intra-hepatic metastasis through its interaction with macrophages.
4. Among all of the TLRs examined, only TLR4 showed an upregulated expression after HCV infection. HCV infection significantly increased IFN-β and IL-6 secretion from B cells and as you know HCV infection could lead to hepatitis, hepatocellular carcinomas, and lymphomas.
There is a fine line between "protection from TLRs" and "damage from TLRs". TLR signaling induces the production of inflammatory mediators and anti-microbial peptides to eradicate invading microorganisms from the host as well as to bridge the acquired immunity to amplify immune responses. However, abnormal activation of innate immune signaling may also cause chronic inflammation, autoimmune diseases, tissue and organ injuries, fibrosis and carcinogenesis. Hepatic inflammation can then cause systemic inflammation followed by the destruction of the intestinal barrier causing leaky gut and bacteria to go from the intestines to the liver. That induces a second activation of TLR signaling in the liver which can cause damage.
HCV's core protein interacts with TLR2 and TLR4 and stimulates various pro-inflammatory and antiinflammatory cytokines. NS3/4A disrupts TLR3 and RIG-1 signaling pathways by blocking TRIF and CARDIF and NS5A interacts with TLR4 and impairs NK cell function. TLR4 is upregulated in T lymphocytes, and MD-2, a TLR4 co-receptor, is increased in monocytes and T cells.
TLR2 correlates significantly with the hepatic necroinflammatory activity grade while TLR4 correlates with the fibrosis stage. TLR 4 expression in pancreatic beta cells affects cell viability and insulin homeostasis. It contributes to the development of insulin resistance and inflammation through its activation by elevated fatty acids and lipopolysaccharide.
High blood sugar, insulin resistance, obesity and lack of sleep cause a low grade chronic inflammation which is associated with expression of TLR4. That may be why Metformin increased SVR in some of the interferon studies. Metformin is a prebiotic and TLR4 inhibitor.
It would be interesting to see whether Metformin can treat leftover side effects from interferon treatment.
Pattern recognition receptors and inflammation.http://www.cell.com/retrieve/pii/S0092867410000231
Toll-like receptor4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells
http://www.ncbi.nlm.nih.gov/ pubmed/12717385
Short-term treatment with metformin suppresses toll like receptors (TLRs) activity
http://www.ncbi.nlm.nih.gov/ pubmed/?term=metformin+and+ TLRs
Looks like TLR4 inhibitors like Metformin can resolve some of interferon's side effects.
https://www.thieme-connect.com/DOI/DOI?10.1055/s-0035-1565207