This is the third of 6 guest posts on infection and chronic disease.
Does chronic IL-6 levels lead to epigenetic changes in DNA methylation that contribute to this pathway?
By Matthew Fitzgerald
How can infection be a carcinogen?
How do infectious diseases lead to cancer, if at all, is still a highly debated area of research. Do infectious diseases change the genetic information by insertions, mutation, or do bacterial toxins act as carcinogens? Does inflammation lead to free radical damage and cancer? While all of these and more are possible causes, another potential mechanism is that infection could change the epigenetics of cells at the site of infection. What is epigenetics? It is how our genetic information is controlled to tell cells what genes should be expressed and what genes should be silenced. For example what tells a stem cell to become a heart cell or kidney cell? Both contain the exact same DNA but are different because they express different genes, this is epigenetics.
(More after the jump…)
Epigenetics and DNA methylation in Cancer
In genetics we learned that there are four bases that comprise DNA, however many researchers today suggest there is a fifth base. No this isn’t the X-files or alien DNA it is methylated cytosine. These cytosines are methylated only at CpG sites in the genome. These CpG’s are frequently found in clusters or “islands” in the promoter region of many genes. Methylation of these cytosines by enzymes called DNA methyltransferases has been shown to help regulate RNA transcription by blocking transcription factors or recruiting proteins to essentially close down the chromatin structure to shut down the gene. This elevated level of cytosine has been reported in almost all tumors and in many tumor suppressor genes such as p16, p14, Rb, Maspin, etc. How does this relate to infection? IL-6 has been reported to effect DNA methyltransferase enzymes and DNA methylation.
IL-6 in Infection, Inflammation and Cancer
IL-6 is a cytokine that plays many roles. It is produced at the site of inflammation and acts to regulate acute phase proteins after infection. It also plays a key role in chronic inflammation. It orchestrates the transition by the body from using neutrophils to macrophages and helps to stimulate T and B cells that favor a more chronic condition of inflammation. Chronic high levels of IL-6 have been reported in patients with numerous chronic diseases: HIV, Hepatitis B and C, arthritis and in many solid tumors such as pancreatic cancer, liver cancer, prostate cancer and others.
IL-6 and DNA Methylation
So it has been shown that chronic high levels of IL-6 is found in patients with numerous diseases such as infection and cancer. What does this high level of IL-6 mean and what could be its effects? Besides its stimulatory effects on cells IL-6 has recently been shown to alter DNA methylation. This could alter a cells gene expression pattern and help lead to transformation to a cancer cell. In a report by Hodge, et. al. in the journal Cancer Research they showed that IL-6 can upregulate DNA methyltransferase(DNMT1). This enzyme is responsible for maintaining the methylation pattern on genes and controlling their expression. They go on to show that high IL-6 expression was linked to the hypermethylation of p53 and a significant decrease in this important tumor suppressors expression. Other researchers have also shown that IL-6 can turn on or off other important genes through methylation, i.e. EGFR, microRNA-370.
Role of IL-6?
This pathway from infection to inflammation to cancer has been widely studied in numerous cancers namely HBV and others but the mechanism of progression to carcinogenesis is still debated. This blog tried to postulate on another possible mechanism that could link these three events. IL-6 is involved to some degree in each of these steps and the recent reports that IL-6 can effect expression through DNA methylation is very interesting. The famous two-hit hypothesis for cancer proposed by Knudson states that two hits such as mutations in oncogenes and silencing of tumor suppressor genes is necessary to develop cancer.
If IL-6 can silence tumor suppressor genes than the other hit could come from other infectious disease insults such as viral genetic insertion into the genome or production of free radicals as a result of chronic inflammation from infection. Too conclude IL-6 is elevated in the sera of numerous patients with infection and chronic disease. While the role of IL-6 in these cases is still being elucidated, IL-6 could have a significant impact at the site of chronic inflammation by altering the epigenetics or gene expression of important genes that lead to carcinogenesis.
While I have studied a couple of papers for this blog post I am by no means an immunologist and it is still too early to say if IL-6’s effect on methylation is a large contributor to cancer. However, it is interesting to think about this cytokines role in chronic disease and the progression towards cancer because it can provide a link from infection to inflammation to cancer.
Matthew Fitzgerald is an RAIII in the Free Radical and Radiation Biology program at the University of Iowa.
Costello and Vertino. 2002. Methylation matters: a new spin on maspin. Nature. 31:123-4. Link.
Hodge DL et al. 2001. Interleukin-6 Regulation of the Human DNA Methyltransferase (HDNMT) Gene in Human Erythroleukemia Cells. 276:39508-39511. Link.
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Porta et al. 2008. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Annals of Oncology. 19: 353-358. Link.
Hodge DR et al. 2005. Interleukin 6 Supports the Maintenance of p53 Tumor Suppressor Gene Promoter Methylation. Cancer Research. 65:4673-4682. Link.
Alpini GD et al. 2007. Genetic and epigenetic changes associated with
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Meng F. et al. 2008. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene. 27:378-386. Link.