July 31 2007 post: MyD88 is an intracellular signaling protein that carries signals from pathogen-associated molecules (translate: biological agents that can cause disease and illnesses, like parasites and viruses and bacteria) to IL-1, an inflammatory cytokine. Wikipedia defines MyD88 as: a universal adapter protein as it is used by all TLRs (except TLR 3) to activate transcription factor Nfkappa B. What are TLRs, you may ask? They are toll-like receptors, or proteins that play an important role (cytokine activation, for instance) in the immune system. I know, I know, this is not easy for me, either! But please bear with me. I do have a point or two to make. And at times I am swimming in very deep (very scientific!) water so if I make a mistake, please let me know.
Why am I writing about MyD88 today? Well, yesterday, as I was looking at the July 2007 issue of Science, my glance fell on this title: Sex, Cytokines and Cancer (http://tinyurl.com/2sq9v6). I must admit that if that article had been titled, e.g., MyD88 and Cancer, I probably would not have been intrigued enough to read it. What can I say? I too like to have a bit of fun with catchy titles, as you may have noticed.
The first part of the article deals with the relationship between cancer and inflammation. It’s an interesting read, so I urge you to go have a look. The authors then examine two studies, published in the same issue of Science. The first, by Naugler et al (see: http://tinyurl.com/237wfb), discusses the link between gender and liver cancer, and the fact that estrogen is an IL-6 inhibitor, which I did not know. The second, by Rakoff-Nahoum and Medzhitov (http://tinyurl.com/2bu9nr), is a study on intestinal cancer. These two researchers discovered that MyD88 stimulates the overexpression of COX-2 and of IL-1, suggesting that this protein promotes and also thrives on cancer. Well, I looked up IL-1 and discovered that it happens to be a MM cell growth promoter, as can be seen in this 2006 Oncogene study: http://tinyurl.com/2wp4sb Indeed, according to another 2006 study (http://tinyurl.com/3294yj), published in the Journal of Interferon and Cytokine Research, IL-1 it is a potent inducer of the important myeloma growth factor, IL-6. This particular study, which compared groups of SMM and active MM patients with low or high IL-1 production, was interesting for another reason. The researchers found that when IL-1 was inhibited, the production of IL-6 in most patients dropped by 90%, leading them to the conclusion that it may be possible to predict patients that will progress to active MM and to delay or prevent this progression with IL-1 antagonists.
DELAY or PREVENT progression? My dream come true!
At this point, a flickering light bulb went on in my head, and I looked up MyD88 and curcumin. Sure enough, curcumin apparently prevents this protein from going about its nasty business. A July 2007 study (http://tinyurl.com/33cjlc), published in the Journal of Leukocyte Biology, discusses bacterial infections and curcumin, and concludes that curcumin inhibits the MyD88-dependent and -independent signaling pathways of LPS signaling through TLR4 [ ]. LPS, by the way, stands for lipopolysaccharide, an endotoxin found inside pathogens (bacteria, e.g.), and TLR4 is another of those above-mentioned toll-like receptors (see Wikipedia for more information on TLRs: http://tinyurl.com/3demwz). A June 2006 study published in Biochemical Pharmacoloy (http://tinyurl.com/2tvjnu) shows that curcumin inhibits both MyD88- and TRIF-dependent pathways in LPS-induced TLR4 signaling. (Note: TRIF, or TIR-domain-containing adapter-inducing interferon-ÃŽÂ², is a signalling pathway that is active mainly in the spleen and is dependent on MyD88.). Oh, and by the way, curcumin downregulates the expression of IL-1, too. A more detailed discussion can be found in Prof. Aggarwal’s 2006 study titled Spicing Up of the Immune System by Curcumin, which I would be happy to forward upon request.
I also discovered that EGCG has the same blocking effect of curcumin against MyD88 (see: http://tinyurl.com/2lrh8r): green tea flavonoids can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs and subsequent inflammatory target gene expression. Now how about that? All this makes me wonder how many more non toxic phytochemicals can inhibit MyD88 ? When I have more time, I must look into this matter more carefully.
Concluding remarks. For the non-scientists among us, this appears to be gibberish, but the basic point is that here we have a couple of non toxic substances â‚¬”curcumin, EGCG â‚¬”that inhibit the activity of a protein, MyD88, essential for the activation of NF-kB. No MyD88, no NF-kB. It seems to be that simple! So if we can block the activity of this signalling pathway, we can also block the effect of inflammatory cytokines that are important, indeed, crucial, for MM cell proliferation and survival. This tiny bit of research (and I barely revealed the tip of the iceberg, there were more studies to be had on this topic, but unfortunately my time is extremely limited today) has given me another reason to keep taking curcumin, and to add EGCG to my future supplement list.