Neuroinflammation plays a crucial role in neurodegenerative diseases

Posted on May 26, 2010 by Dr. Jonathan

This excellent review published recently in the journal Molecular Neurodegeneration elucidates the epidemiologic, pharmacologic and genetic evidence that explains why inflammation in the brain and the rest of the central nervous system is a key factor in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis.

“While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults.”

Inflammatory stimuli include allergens (gluten, etc.), infections, trauma, neurogenic activation of the inflammatory response, and others. Microglia (the immune cells in the brain) are activated and release inflammatory mediators, the cytokines and chemokines that we measure with lab tests.

“…chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult.”

Once chronic neuroinflammation has been established, these inflammatory mediators perpetuate a cascading inflammatory cycle.

Neuroinflammation, neuronal dysfunction and degeneration

“Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines.”

In other words, microglial activation and the chronic inflammation it perpetuates is the convergence point for all the kinds of stimuli associated with these neurodegenerative disorders as well as many other conditions affected by compromised brain function. This is partly why it is of such great practical importance to profile immune dysregulation in the central nervous system with the appropriate lab tests as a basis for rational therapy.

Mechanisms that link inflammation, obesity and cancer

Posted on May 5, 2010 by Dr. Jonathan

The latest issue of the Journal of the National Cancer Institute comments on recent research investigating how the inflammatory cytokines (cell signaling molecules), which are increased under various conditions that include obesity, can turn healthy liver cells into malignant ones:

“As obesity’s ties to multiple cancers strengthen, a new study suggests that inflammation may be the primary culprit in at least one malignancy: liver cancer.”

Cell The study itself was recently published in the journal Cell. The report that…

“We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice…Obesity-promoted HCC (hepatocellular carcinoma = liver cancer) development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3.”

Readers here will not be surprised that they also assert…

“The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.”

Three important points: (1) nothing increases the storage of fat in the liver like the high levels of insulin associated with insulin resistance (remember the link between insulin and fatty liver disease). (2) Chronic inflammation, whatever the cause, is a component of most chronic degenerative diseases. (3) Those of us who are health care professionals should be using the available laboratory tests for inflammatory cytokines in the care of our patients when appropriate; readers who are patients should be asking about them.

Depression involves brain inflammation

Posted on April 1, 2010 by Dr. Jonathan

Biological Psychiatry Not to oversimplify since depression can have multiple contributing causes, but there have been many studies published about brain inflammation as an important component of major and minor depression. An illuminating paper published in the latest volume of the journal Biological Psychiatry undertakes an extensive analysis of accumulated scientific evidence. The authors begin by noting:

“Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls.”

Cytokines are, among other things, signalling molecules that regulate immune system function. This has great practical significance because there is an evidence-based approach in functional medicine to analyzing and treating cytokine imbalances. The authors evaluated 24 studies that included eight different cytokines. Here’s what their data showed:

“This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects…this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.”

You may enjoy the interesting comment on this study just published in Journal Watch.

Although this is a valuable study it’s important to keep a broad perspective. Here’s another paper published not long ago in the journal Pharmacopsychiatry, one among many others on cytokines and depression. It documents cases of brain inflammation with a different cytokine pattern. This paper is also interesting for the therapeutic comparison of Prozac and electroacupuncture:

“An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines.”

Th1 and Th2 are the two primary poles of immune system function, cell-mediated and humoral (antibody). Imbalances result in immune dysregulation. Fluoxetine is Prozac. (The inclusion of electroacupuncture might tip you off that this study was done in Germany.) Their data tells a fascinating story:

“Increased proinflammatory cytokine interleukin (IL)-1β and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contrast, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients…Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1β concentrations in responders. However, only acupuncture attenuated TNF-α concentration and INF-γ/IL-4 ratio towards the control level.”

How interesting that what we call a peripheral sensory nervous system modality (stimulation of the brain through the peripheral sensory nerves, in this case with electroacupuncture) reduced inflammation and TNF-α. This corresponds exactly with my clinical experience employing these modalities for a range of conditions including autoimmune disorders, and explains part of why patients feel so much better after a treatment. Their conclusion is worth noting:

“These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-γ or TNF-α and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1β. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-α and decreasing IL-4.”

Thus depression involves inflammation, but the cytokine expression can vary.

This topic is multifaceted and a proper synopsis of the functional approach to depression is too long for this forum, but here’s one more paper to keep the horizon open. This study published not long ago in the Journal of Psychiatric Practice investigates the role of low testosterone in depression.

“Studies suggest that testosterone (TT) replacement may have an antidepressant effect in depressed patients…The objective of this study was to explore the effect of TT administration on depression using both a systematic review of the literature and a meta-analysis.”

What did the data show?

“Meta-analysis of the data from these seven studies showed a significant positive effect of TT therapy on…depressed patients when compared with placebo. Subgroup analysis also showed a significant response in the subpopulations with hypogonadism…”

This certainly confirms expectations considering the population of testosterone receptors in the brain and their density in the frontal lobe. Hypogonadism means that the testicles are producing too little testosterone in response to stimulation by luteinizing hormone (LH). This validates my common sense practice of always including biologically active free fraction testosterone and LH in workups for male depression. Note: testosterone replacement, especially by a transdermal route (gel, patch, cream) can give a good initial result but end up back-firing. This is a topic for another post. For now just remember there is a better way.

Cancer, TGF-β and curcumin

Posted on March 31, 2010 by Dr. Jonathan

Cytokines are signalling molecules that orchestrate immune system activity, among which TGF-β (Transforming Growth Factor-Beta) is being recognized by numerous studies to have an important role in the immune response to cancers.

The authors of a paper just now being published in the European Journal of Cancer note the dual activity of TGF-β, and acknowledge that related treatments are being pursued:

“Transforming growth factor (TGF)-β signalling plays a dichotomous role in tumour progression, acting as a tumour suppressor early and as a pro-metastatic pathway in late-stages. There is accumulating evidence that advanced-stage tumours produce excessive levels of TGF-β, which acts to promote tumour growth… In light of the pro-metastasis function, many strategies are currently being explored to antagonise the TGF-β pathway as a treatment for metastatic cancers.”

A similar paper published in the journal Expert Opinion on Investigational Drugs also states:

“The transforming growth factor-ß (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes. TGF-β switches its role from a tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers.”

They too note the enthusiasm for TGF-β inhibition in developed malignancies:

“TGF-β signaling has been considered a useful therapeutic target. The discovery of oncogenic actions of TGF-β has generated a great deal of enthusiasm for developing TGF-β signaling inhibitors for the treatment of cancer.”

A review published a month later in Expert Opinion on Therapeutic Targets considers inhibition of TGF-β specifically for prostate cancer:

“TGF-β regulates prostate growth by inhibiting epithelial cell proliferation and inducing apoptosis through eliciting a dynamic signaling pathway. In metastatic prostate cancer, however, TGF-β serves as a tumor promoter.”

They define very nicely the need to take a balanced approach in consideration of the dual role of TGF-β:

“”The molecular basis for effective therapeutic targeting of TGF-β must be directed towards the double-edge-sword nature of the cytokine: Inhibiting the TGF-β tumor promoter capabilities in advanced metastatic prostate cancer, although retaining the growth-inhibitory abilities exhibited in early stages of prostate tumorigenesis.”

Cellular & Molecular Biology Now consider this fascinating research just now being published in the journal Cellular & Molecular Immunology on the ability of curcumin (an extract of turmeric) to reduce the undesirable action of TGF-β. The authors begin by observing:

“Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion…Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells.”

Interestingly, not only did curcumin prevent the loss of T cells and reverse the type 2 immune bias…

“Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-β and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-β and IL-10 in these cells…curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.”

You may also wish to read an earlier post on cytokines and prostate cancer. I hope this makes it clear why I consider the measurement of TGF-β an important laboratory test for my patients in these circumstances, and curcumin a potentially valuable therapeutic ally. Be sure to discuss these with your doctor if the need arises.

The importance of testing cytokines: prostate cancer

Posted on February 7, 2010 by Dr. Jonathan

There are many studies that demonstrate the importance of testing cytokines (‘messenger molecules’ of the immune system) for prostate cancer. One paper published some time ago in the Journal of Clinical Oncology examined whether the cytokines IL-6 Soluble Receptor and TGF-Beta can predict if clinically localized prostate cancer will progress or not. The authors demonstrated that measuring IL6SR and TGF-β1…

“…improved the ability to predict biochemicalprogression by a prognostically substantial margin.”

In other words, this helps determine who needs a more aggressive intervention and who doesn’t.

The authors of a paper published in the journal Clinical Cancer Research investigated how cytokines before and after surgery correspond to prostate cancer progression:

“We have shown that preoperative plasma levels of transforming growth factor-β1 (TGF-β1), interleukin 6 (IL)-6, and its receptor (IL-6sR) are associated with prostate cancer progression and metastasis. The objectives of this study were to…examine the association of …these markers after surgery with disease progression in a large consecutive cohort of patients.”

Their conclusion:

“For patients undergoing radical prostatectomy, preoperative plasma levels of TGF-β1 and IL-6sR are associated with metastases…and disease progression. After prostate removal, postoperative TGF-β1 level increases in value over preoperative levels for the prediction of disease progression.”

Another study demonstrating that cytokines greatly increase the accuracy of predicting the potential for prostate cancer recurrence was published in the journal The Prostate. The authors set out to test…

“the ability of several pre-operative blood-based biomarkers to enhance the accuracy of standard post-operative features for the prediction of biochemical recurrence (BCR) after radical prostatectomy (RP).”

They measured the cytokines IL-6, ILsR and TGF-β and concluded:

“Pre-operative plasma biomarkers improved the accuracy of established post-operative prognostic factors of BCR by a significant margin. Incorporation of these biomarkers into standard predictive models may allow more accurate identification of patients who are likely to fail RP thereby allowing more efficient delivery of adjuvant therapy.”

The importance of testing cytokines: rheumatoid arthritis

Posted on February 5, 2010 by Dr. Jonathan

It has come to my attention that many doctors remain unfamiliar with the clinical value and importance of testing (blood) cytokines. Cytokines are ‘messenger molecules’ of the immune system involved in the regulation of inflammation. Knowledge of their levels helps not just with early diagnosis and prognosis, but can profile immune system imbalance allowing functional treatment to be precisely targeted and bad reactions avoided (even Echinacea can push some people’s immune system in the wrong direction). There are thousands of studies on clinical conditions for which this is important. Here ‘s one for rheumatoid arthritis:

Arthritis & Rheumatism Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis

This study recently published in the journal Arthritis & Rheumatism (the journal of the American College of Rheumatology) set out to “identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).” Their conclusion was in line with findings of other investigators: “Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors.”

Different genes = different response to vaccines

Posted on December 7, 2009 by Dr. Jonathan

I hope that readers who are less familiar with the science and evidence-based approach of functional medicine are able to appreciate the significance of this paper that was recently published in the journal Vaccine. The authors state: “The magnitude of the immune response to vaccinations can be influenced by genetic variability.” This could, if attention is paid, bring more urgently needed research to bear on the critical principle at the heart of the benefits and risks of vaccination: individuals respond to vaccines differently. The investigators demonstrated that differences in the genes that code for cytokines (‘messenger molecules’ for the immune system) were clearly associated with variations in the immune response to childhood vaccination, with some children not gaining any immunity at all. The authors conclude: “These data suggest that genetic variations in cytokine genes can influence vaccine-induced immune responses in infants, which in turn may influence vaccine efficacy.” We need a sound vaccination policy that establishes a standard of care using cost-effective evaluations to determine for each person their capacity to benefit from a vaccine, along with any predisposition for autoimmune reactions that could manifest at a later date.

Controlling inflammation and hypertension help prevent Alzheimer’s

Posted on November 25, 2009 by Dr. Jonathan

If you have a parent who has suffered from Alzheimer’s disease, this paper just published in the Archives on General Psychiatry identifies two vascular factors that you can use for screening and prevention: hypertension (high blood pressure) and pro-inflammatory cytokines (signaling molecules that promote inflammation). The authors conclude: “Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies…” Blood tests that measure cytokines are available at a discount due to our co-op association with Labcorp.

Chili pepper reduces obesity-induced insulin resistance & liver fat

Posted on November 1, 2009 by Dr. Jonathan

This welcome study demonstrates that capsaicin (the chemical that makes chilies hot) “lowered fasting glucose, insulin, leptin levels, and markedly reduced the impairment of glucose tolerance.” Levels of inflammatory cytokines (signalling molecules that increase inflammation) in fat and liver tissue also “decreased markedly”. Adiponectin (the hormone secreted in fat tissue that reduces body fat, type 2 diabetes, blood vessel deposits and fatty liver disease) was increased, along with other beneficial agents. “Our data suggest that dietary capsaicin may reduce obesity-induced glucose intolerance by not only suppressing inflammatory responses but also enhancing fatty acid oxidation in adipose tissue and/or liver.” So eat chili peppers to burn fat, suppress inflammation and improve glucose tolerance.

Proinflammatory Cytokines Increase After Menopause

Posted on October 22, 2009 by Dr. Jonathan

There is much more going on in menopause than a decline in hormone production by the ovaries. This paper published earlier in Endocrine Reviews, the journal of the Endocrine Society, discusses the increase in cytokines (a class of signalling molecules) that upregulate inflammation throughout the body (a feature of all chronic diseases including neurodegeneration, osteoporosis, cardiovascular, cancers, etc.). Two startling facts:

The inflammatory cytokines remain elevated even after estrogen replacement.
Cytokine receptors throughout the body also increase in activity.

A natural anti-inflammatory strategy is mandatory for a healthy menopause, ideally beginning well before.