Monday, October 27, 2014

Inflammation IL 6 NF κB and disease

Inflammation is a part of the bodys immune response that has been implicated in a number of disease conditions, such as atherosclerosis, diabetes, osteoporosis, and cancer. Previous posts on the subject can be found here, here, here, and here.

Much of the research discussed in those posts reports on some correlation found between markers of inflammation and occurrence of disease. What we really want, however, is to understand the underlying mechanisms that might explain the correlation. Here well take a look at one of the hypothesized mechanisms.

This article: The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases is a fascinating but technical and difficult review article that makes the daring claim that
Inhibition of the signal transduction pathway for Interleukin 6 mediated inflammation is key to the prevention and treatment of aging and age-related disorders including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia, Alzheimers disease and some forms of arthritis and cancer.

Be forewarned, if you undertake to read the article, that it presumes at least a passing knowledge of biochemistry, the mammalian immune system, and the physiology behind diseases such as diabetes and cardiovascular disorders. In addition, it could be better written, with clearer development of its central arguments. Finally, its contention as quoted above is a sweeping, far-reaching hypotheses that will require much additional research to establish securely.

It is also possible that there is some element of hype in the claims made. One should always adopt a skeptical attitude towards a declaration that anything like a potential "fountain of youth" has been discovered.

This hypothesis may well be too broad. Nevertheless, the paper provides an excellent means of focusing discussion on a number of important topics that seem to be linked inevitably to strategies for preventing or delaying the onset of the aging and age-related diseases listed above. Who could fail to find that prospect interesting?

So well begin with some setting of the stage. Inflammation is a major feature of the mammalian immune system, which employs the vascular system (among other things) to mount a response to infections, damaged cells, and other harmful stimuli. For example, signaling proteins, known as cytokines, are dumped into the blood stream to attract the attention of other components of the immune system, such as white blood cells (leukocytes), which then migrate through the blood stream to the site of the problem.

Several cytokines play an important role in the inflammatory process. The list includes Interleukin-1 (IL-1), Tumor Necrosis Factor α (TNF-α), and Interleukin-6 (IL-6). Of these, the last, IL-6, is singled out for special attention, because it appears to be especially important in the inflammatory process itself. Control of the process is important, because research implicates an excessive or overactive inflammatory response as a significant factor in the diseases of aging listed above.

Control of IL-6, in turn, may depend on control of the protein NF-κB (Nuclear Factor κB), which is a transcription factor that is thought to be necessary for the expression of the gene for IL-6. NF-κB is an essential part of the signaling pathway through which IL-6 is produced. Without activated NF-κB there may be no IL-6. However, NF-κB is also implicated in a number of other physiological processes as seemingly independent from the inflammatory response as synaptic plasticity and memory. This poses a challenge to any attempt to regulate the inflammatory response by regulating NF-κB.

As we shall see in subsequent postings, theres a lot of very interesting research going on related to the role of inflammation in disease in general, and with the involvement of NF-κB in particular.

Well describe here just a couple of the recent examples.

Key To Out-of-control Immune Response In Lung Injury Found
Acute Respiratory Distress Syndrome, or ARDS, is an often fatal complication of severe traumatic injury, bacterial infections, blood transfusions and overdoses of some medications. In ARDS, the lungs become swollen with fluid and breathing becomes impossible. ...

Sepsis, an overwhelming bacterial infection of the blood and organs, is the most common cause of ARDS. When the immune system responds to the infection, molecules called inflammatory cytokines and chemokines are released. These molecules attract inflammatory white blood cells and destroy bacteria, but also lead to fever, swelling and other symptoms of shock and can wreak havoc on the patient in the course of fighting off the infection.

The researchers worked with a strain of mice that lacked a gene called Cblb. This gene codes for a protein that disables a cell surface receptor. Unless this receptor is disabled it will keep NF-κB activated, and therefore leads to the overproduction of inflammatory cytokines. The result is a "cytokine storm" that leads to ARDS-like symptoms and greater likelihood of fatal results for the Cblb-deficient mice:
When sepsis was induced in mice with and without the Cblb gene, there was a marked difference in the level of the inflammatory response and survival. Mice lacking the Cblb gene were much less likely to survive than control mice.

It shouldnt be concluded, however, that NF-κB (or IL-6 for that matter) is intrinsically harmful. If that were the case, it would not be so widely conserved in evolution, as it is. NF-κB is found even in the simplest of animals, such as corals, sea anemones, and sponges.

As noted, NF-κB is a transcription factor for a number of genes besides IL-6. Some of these genes code for proteins that promote cell survival and proliferation. This, too, can be a double-edged sword, as with inflammatory cytokines. In particular, it appears that NF-κB plays a non-trivial role in various types of cancer. Well write about that in another article. However, the following research seems to demonstrate a case where the cell survival role of NF-κB predominates:

Researchers Identify Molecular Basis Of Inflammatory Bowel Disease
[Researchers] generated a mouse model that does not express NEMO, a protein needed to activate NF-κB, in intestinal epithelial cells. As a result, these mice developed severe chronic intestinal inflammation very similar to Colitis in humans.

"A close look at the mice revealed that their gut epithelium was damaged," says Manolis Pasparakis, who recently moved from heading a lab at EMBL to becoming a professor at the University of Cologne. "NF-κB acts as a survival signal for cells. Without the molecule cells are much more likely to die and this is what happened in the intestines of our mice; individual epithelial cells died disrupting the gut lining."

Through these gaps bacteria could penetrate the intestinal wall. Right behind the gut epithelium lie cells of the intestinal immune system, the biggest immune system of our body. It detects the invading bacteria and generates a strong immune response to fight off the invaders. In the process of combating the bacteria, the immune cells secrete a cocktail of signals that bring about the symptoms of inflammation.

"This is where the vicious cycle closes," explains Markus Neurath, professor at the University of Mainz. "Inflammatory signals also reach the epithelial cells that due to the lack of NF-κB are very sensitive to them and die. The death of more epithelial cells creates bigger gaps in the gut lining so that more bacteria enter. The result is a constant immune response leading to chronic inflammation as we know it from inflammatory bowel diseases in humans."

Tags: inflammation, immune system, IL-6, interleukin-6, NF-kB, aging

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