Kevin Spelman - molecular bio of immunomodulators

From the AHG symposium

Immunomodulators: botanical medicines that through the dynamical regulation of informational molecules alter the activity of the immune systems.

Cytokines and the cytokine theory of disease (Czura, CJ 2005): overproduction of cytokines can cause the clinical manifestations of disease. But it can begin on an emotional level (anger/shame as opposed to medidative states) - then as cytokines levels increase, disease manifests: first depression, pain, anorexia. Then, psoriasis, colitis. Then, tissue damage and arthritis. Finally, shock and organ failure.

Tumor necrosis factor (TNF) and other cytokines like Epidermal Growth Factor stimulate a series of intracellular changes that ultimately have effects in the nucleus - on genetic expression. When, in researching botanicals, we look at the nucleus, we're getting somewhere.

Paul Ridker MD 2002: "It may be possible that having a high cytokine response in our evolutionary past served us well, when our lifespan was 35-40 years. Insulin resistance might have been useful (to prevent starvation). Not so anymore."

The effect of cytokines depends on the cell secreting it (lymphocytes, monocytes, etc) and the physiological context in which they are secreted. They are "immune hormones". Subtypes:
-interleukins, which have profound effects on inflammation, immunity, central nervous systems, hormone secretions (esp. ACTH, corticoids), they drive antibody response.
-interferons, which are the first line of defense against viruses. They are also cytotoxic, disrupt sleep and HPA axis, stimulate fever-like response.
-colony stimulation factors, which affect cell motility and proliferation, wound healing, inflammation, and hematopoiesis
-chemokines, which stimulate chemotaxis, immune function, inflammation.

Cytokines are versatile. They have different roles, redundancy, synergy and antagonism, and can be autocrine, paracrine, or systemic in their actions. Cytokine receptors are membrane bound, though some are freely floating and act as an activating complex. They are secreted and produced for short periods of time, with little storage and tight regulation of production, and super-short half-lives - "like fireflies".
Normal physiologic functions that induce cytokine production are sleep (to repair/renew) and ovulation. Production in healthy tissue is minimal. Microbial infection, other cytokines, stress, corticoids, histamine all stimulate cytokines as well. "This is why hayfever can actually make you feel really sick".

We are attempting to exploit cytokines pharmacologically. Stimulate, inhibit, block, activate. Herbal medicines have been doing this for a long time. For example, now we use interferon for hepatitis, melanoma, lymphoma. TNF-alpha inhibitors are used for rheumatoid arthritis. Interleukins and interleukin inhibitors are used for asthma modulation, to reduce the risk of Alzheimers.

What about further, bigger thinking on cytokine use? They're implicated in all chronic, age-related, inflammatory diseases. They travel broadly throughout the body. They may also have huge behavioral effects (if we buy in to the psycho-neuro-immunology - PNI - model). Why do we get grumpy when we have the flu? Cytokines. But the behavior also isolates us, separating us from the herd, to protect our peers from infection.
Liver, heart, vessel walls, and adipose tissue all produce cytokines, and may contribute to the etiology of cardiovascular disease. The liver is dear to herbalists - for so many good reasons.
Diseases such as anorexia, schizophrenia, depression, Alzheimer's all show high plasma levels of cytokines. These can be directly measured (though the tests are expensive right now). What we still need clarity on is defining the normal range (which right now is super-wide). Maybe we can get there through genetic medicine, by refining the "normal" depending on genome. Herbalists, however, have always had a good differentiating tool: the constitution. Perhaps pitta people, for instance, exhibit higher "normal" ranges of cytokines.

Adhesion molecules (cellular adhesion molecules - CAMs) are immunoglobulin superfamily CAMs (IgSF - CD-x cell surface receptors), integrins, cadherins, selectins. They are involved in embryonic development, neuro development, tissue adhesion, and expressed by leukocytes, platelets, epithelial and endothelial cells. They maintain tissue integrity, and recruit cells to tissues. They have a critical role to play in pathology, cancer. There are higher levels in those at risk for heart attacks. They may also be involved in behavior - though the research is preliminary (Walzog, B 2000).
The conformation of adhesion molecules - extended versus bent - has an important role to play in the ability of adhesion molecules to function.
Adhesion molecules are important in inflammation - for example, p-selectins expressed on the endothelium sticks to sugars on white blood cell membranes and get snagged there. Then, integrins on white blood cells actually cause the WBC to stop, so it can engage in diapedesis (move across the vessel wall). In the wrong conditions, with too much inflammation, this leads to plaque formation in the vessel wall - atherosclerosis. It may also be important in perpetuating inflammation in autoimmune disease.

Next, nitric oxide (NO) starts to be produced. It is a free radical, second messenger, paracrine, vasodilative, neurotransmitter, and hormone. Signal molecule in the vasculature, neurons and immune system. It can act within the cell, moves through water and fat, and readily diffuses. It's synthesized from arginine (sister amino acid to lysine - they are in counterbalance to each other) using nitric-oxide-synthases. Interestingly, arginine levels are high in veg protein (peanuts, e.g.) and lysine high in animal protein.
The enzyme nitric-oxide-synthase is the key intervention point. It needs cofactors: NADPH, FAD, FMN (all based on B-vits) all linked by a calmodulin binding site [note from Guido: calmodulin found in, and stimulated by, milky oats]. Eventually, NO activates smooth muscle cAMP which relaxes the muscle.
Another important NO stimulating factor (through eNOS activation) is shear stress on the endothelium: often caused by high blood pressure.
NO not only leads to vasorelaxation, but also decreases platelet aggregation.
iNOS, which is created on an as-needed basis, often comes from macrophages when they are activated. So extra NO is produced when needed by immune cells! This vasodilates, sure, but NO is also a free radical that the immune players "shoot out" to damage invaders. Unfortunately, though, it can also damage us. Interferon is often the cytokine that gets iNOS going by activating iNOS gene expression.
nNOS (neuronal-nitric-oxide-synthase) is stimulated through a glutamate-sensitive NMDA receptor. The nitric oxide produced as a result enhances memory and learning. It's crucial for this purpose.

When NO is broken down, it produces superoxide ions, nitrates, and perhaps also peroxinitrites (ONOO-) which has been implicated as a cause of chronic fatigue syndrome (cf. Pall). It's extremely toxic, and will uncouple oxydative phosphorylation in the mitochondria - you can't make ATP anymore! If we remember that, because inflammation can come from infection, inflammation, or emotion, NO can come from a variety of causes, chronically elevated levels can lead to profound fatigue.
"We should be looking at the common molecular basis for disease, rather that all these different disease labels. This is part of the future of medicine".

Angelica sinensis: inhibits adhesion molecules, reduces iNOS
Curcuma spp.: modulates adhesion molecules, reduces iNOS. Very pleiotropic. A variety of constituents with multiple countervalent effects - depending on cell type and physiological context.
Echinacea purpurea: countervalent effects on cytokines (TNF), interleukins, selectins and iNOS. It has a lot to do with the dose and research model (in vitro) presenting different conditions. Also, extraction has a huge role to play: European products, for instance, often have low alkylamide content.
Ginkgo biloba: inhibits adhesion molecules, reduces iNOS.

Spelman - 2008: Modulation of Cytokine Expression by Traditional Medicines

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