"All roads to chronic disease lead through inflammation."^1-3 This concept has driven the evolution of understanding of the etiology of chronic diseases since the discovery in 1988 by David Baltimore of nuclear factor kappa B (NF-kB) as a regulatory factor stimulating inflammatory gene expression, and the relationship of its activity to chronic diseases as divergent as heart disease, arthritis, asthma, dementia, osteoporosis, and cancer.⁴

The recognition that inflammation is the "root of all chronic illness" has resulted in the view that the solution to the epidemic of chronic diseases may lie in the discovery of the universal anti-inflammatory or NF-kB inhibitor that could be used in both the early-stage prevention and treatment of all the conditions associated with inflammation. Before we jump on this bandwagon, however, there are a number of confounding issues that we must be aware of.

First, inflammation exists in many forms, which can range from chronic to acute. Triggers that precipitate inflammation can be pathogenic, traumatic, ischemic, toxic, and allergic. Each of these forms of inflammation has differing tissue specificity driven by distinct cellular inflammatory signaling mechanisms.⁵

Second, the inflammatory response is unique to the genotype of the individual, thereby modifying the cellular specificity and magnitude of the inflammatory response to a specific trigger.⁶

Case History: Alzheimer's Disease and Anti-Inflammatories
As a clinical case in point, a review of the connection between Alzheimer's disease and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) deserves mention. In a 1993 report of a 6-month trial, the NSAID indomethacin appeared to protect mild to moderately impaired Alzheimer's disease patients from further cognitive decline compared with a control group.⁷ In 1994 a co-twin retrospective study reported that among elderly twins, the twin using NSAID medications seemed to have a delayed onset of Alzheimer's disease.⁸ This was followed up in 1995 when a report of an evaluation of medical records from Alzheimer's patients revealed that those who used ibuprofen on a regular basis seemed to have a slower progression of the disease.⁹ All of these observations seemed plausible given the increasing understanding of the etiology of Alzheimer's disease as having an inflammatory component.¹⁰

The story of the connection be­tween reduction in Alzheimer's disease and the use of NSAIDs has, however, become more complicated over the past few years.¹¹ A report in 2010 indicated that the heavy use of NSAIDs by Alzheimer's patients resulted in an increase rather than a decrease in the neuritic plaques associated with the disease.¹² This may be due to the fact that systemic inflammatory cells have now been identified as important in fighting off the progression of neurodegenerative disease, and therefore "too much of a good thing" related to anti-inflammation might be contraindicated.¹³ This might help to explain the results from the Adult Changes in Thought (ACT) study that found a worsening of symptoms over 12 months in a multicentered clinical trial with Alzheimer's patients taking various NSAIDs, including ibuprofen.¹⁴ Another intervention trial found that patients with early-stage Alzheimer's disease who were administered NSAIDs seemed to have a delayed development of the disease, but those with later-stage disease have an accelerated development of the disease with NSAID treatment.¹⁵ This suggests that preventing inflammation with NSAIDs in the early stage of the disease could be valuable, but in the later stage of the disease, preventing inflammation, which represents the body's positive response to the disease, might be contraindicated.

This raises a central question as to whether inflammation is the primary cause of any disease, or rather a secondary adaptive response to a disturbance in cellular physiology, resulting in the activation of the inflammatory response as a component of the healing response. If this is true, then successful intervention could require a specific type of modulator of inflammation whose mechanism of action is not universal for quenching all forms of inflammation, but rather selective for the physiological pathways that are associated with inflammation of a specific pathology. The most potent or broadly acting anti-inflammatory may not be the best choice for producing the most favorable longer-term outcome. Therapy that is tailored to tissue-specific inflammation and to the genotype of the individual patient is emerging as a more successful approach. This has been derived from research on the NSAID-Alzheimer's disease connection which indicates that a specific apo E4 allele genotype seems to be the only genotype that is responsive to NSAIDs in the reduction of Alzheimer's dementia.¹⁶ In this study of multiple NSAIDs, there was no benefit from the use of NSAIDs that was focused on the reduction of a beta amyloid protein, suggesting that the concept of successful intervention with an "anti-inflammatory agent" must be mechanism-, genotype- and condition-specific to provide clinical benefit.

Inflammatory Nuclear and Mitochondrial Transcription Factors
The story that relates the use of anti-inflammatory agents for the management of chronic disease becomes even more complex given the recent report that the control of inflammatory gene expression and the production of inflammatory cytokines such as interleukin 6, chemokines, eicosanoids such as the leukotriene B4 and prostaglandin E2, and inflammatory proteins such as C-reactive protein (hsCRP) are tightly regulated through the production and activity of nuclear and mitochondrial transcription factors.¹⁷ The best known of these transcription factors is NF-kB. There are, however, many other transcription factors that regulate inflammatory gene expression, including AP-1, CREB, NFAT, USF 1 and 2, nuclear orphan receptors such as PPAR, and the vitamin D, retinoic acid, and thyroid hormone receptors.¹⁸ All of these transcription factors that relate to the control of inflammatory gene expression have been found to have multiple genetic poly­morphisms that further compli­cate clinical decision-making with regard to what is the most appropriate anti-inflammatory.¹⁹

What has been discovered over the past 10 years is that the control of inflammatory signaling at the cellular level is closely integrated with many other cellular regulatory functions such as insulin signaling, mitochondrial bioenergetics/cellular redox, and detoxification.^20-24

Posttranslational Modification of Transcription Factors and Inflammatory Signaling Molecules
It is also known that nuclear and mitochondrial transcription factors and inflammatory signaling molecules such as pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin 1 (IL-1), and interferon gamma (IFN-g), can be posttranslationally modified in the cell by other processes, including protein phosphorylation by specific kinase enzymes.^25,26 For instance, NF-kB itself can be posttranslationally modified by phosphorylation at various sites on its structure. The result of this phosphorylation by specific kinases is to change the function of NF-kB so that there are many "voices" of NF-kB available depending upon its phosphorylation state. This is one reason why a nonspecific NF-kB-inhibiting drug may pose a safety and efficacy problem due to the potential range of unexpected influences and physiological effects that it could have on the complex NF-kB-regulated process.

It has recently been discovered that omega-3 fatty acids modulate inflammation in part by their influence on the regulation of specific kinase signaling pathways that control nuclear regulatory factor activity and inflammatory gene expression.^27,28 Supplementation studies in humans with omega-3 EPA and DHA have demonstrated their impact on regulating inflammatory pathways without blocking the housekeeping inflammatory functions.^29,30 These mechanistic characteristics of this class of bioactive food-derived substances impart a unique safety and efficacy profile from those of traditional anti-inflammatory drugs such as NSAIDs.

The trajectory of the development of new anti-inflammatories is focused on substances that influence the upstream regulation of inflammatory gene transcription in a tissue-specific manner and direct cellular function toward a favorable control of "friendly" inflammatory function, while inhibiting pathological inflammation. This can best be accomplished by modulating the regulatory factors controlling the translation of a trigger for inflammation into pathological inflammation, rather than by blocking downstream enzymes such as cyclooxygenases or lipoxygenases that control the last stages of the inflammatory process and thereby have low levels of tissue specificity.

Kinases and the 'Upstream' Control of Inflammation
There are over 300 protein kinase enzymes that control specific posttranslational process through selective phosphorylation. These regulatory kinase processes provide for a tightly controlled orchestration of integrated cellular function, including inflammation, cellular division, bioenergetics, detoxification, and biosynthesis of regulatory substances that control metabolism. Over the past seven years, the Metagenics Nutrigenomic Research Center (Gig Harbor, Washington) has been involved in exploration of how substances from food and spices influence this complex kinase network in a tissue-specific manner. The result of these efforts is the discovery of how specific phytochemicals "speak to the genes" through modulation of the kinase network, thereby attenuating inflammatory gene expression in a tissue-specific fashion.^31-33 This represents a very different clinical approach to the management of inflammatory disorders than the traditional therapy focused on blocking a specific "downstream" inflammatory substance such as PGE2, TNF-a, leukotriene B4, or NF-kB. Rather, this approach harnesses the biological control of inflammation built into nature through the kinase regulatory process to influence in a tissue-specific manner the "upstream" inflammatory gene expression without blocking the desirable "housekeeping" inflammatory processes. This clinical approach to the management of pathological inflammation provides for an outcome that is less likely to adversely influence off-target tissues.

Clinical Implications of the 'Upstream' Approach to Managing Inflammation
The clinical assessment of inflammation generally begins with evaluation of its traditional hallmarks, rubor, tumor, calor, and dolor (redness, swelling, heat, and pain). In the case of chronic systemic inflammatory conditions associated with chronic illness, these clinical signs may be occult. Due to this uncertainty of a diagnosis by clinical signs alone, specific serological biomarkers have been discovered that relate to systemic inflammation, including C-reactive protein and its more sensitive relative hs-CRP, amyloid A protein, uric acid, IL-6, TNF-a, and calprotectin. These markers are not tissue specific, but rather indicative of a relative shift in the immune system toward systemic pathological inflammation. The differential assessment of the particular tissue type of inflammation such as cardiovascular, hepatic, neurological, or musculoskeletal inflammation may require more specific testing such as antibodies to specific tissues (i.e., ANA, anti-CCP antibodies, antithyroidal antibodies), or biomolecules that have been modified as a result of inflammatory processes (i.e., advanced glycation end products, oxidized lipids and protein, or damaged DNA such as 8-hydroxy-deoxyguanosine).

We have reported over the past five years in several published intervention studies that people with chronic inflammation associated with arthritis, insulin resistance, and osteolysis of bone, when treated with anti-inflammatory agents derived from natural products that mildly modulate specific kinases associated with chronic inflammation, have favorable clinical outcomes. These results are in direct opposition to those of interventions with anti-inflammatory therapies that have a principle mechan­ism of action to inhibit cyclo­oxygenases or lipoxyganases down­stream, commonly producing significant off-target side effects to the intestinal tract, vascular endothelium, or liver.^34-41 Recently we reported that specific phytochemical selective  kin­ase response modulators of inflammation were safe to the gastro­intestinal mucosa over an extended period of administration as a result of a distinct mode of action, in contrast to traditional cyclooxygenase inhibitors that have significant gastrointestinal risk with long-term use.⁴²

It is remarkable that over the past 10 years, a scientific and clinical literature has emerged that describes not only the complexity of the inflammatory process, but also how substances that have been consumed as components of humans' traditional diets can serve as modulators of the inflammatory signaling process.⁴³ It is now clear that evolutionary processes resulted in a very remarkable physiological relationship between humans and the bioactive components of their food. Many phytochemicals that are secondary metabolites in plants have been identified to be "antistress" compounds for the plant. These compounds that are present in the human diet are now being found to be bioactive substances that modulate, in a very "intelligent" manner, the inflammatory response.⁴⁴ These recent discoveries, when coupled with the increasing understanding of the inflammatory process, may pave the way to the development of much safer and more effective anti-inflammatory substances for long-term use in conditions associated with chronic inflammation.

Conclusion
The clinical takeaways from this discussion are the following:
1.  There are multiple types of inflammation.
2.  Chronic inflammation is associated with many chronic diseases.
3.  There are multiple cellular mechanisms that result in chronic inflammation localized in specific tissues.
4.  There are multiple genotypes that respond to different inflammatory triggers with unique clinical outcomes.
5.  Uses of anti-inflammatories that lack tissue specificity are associated with off-target adverse clinical effects.
6.  Biological response modifying substances with a mechanism of action that is "upstream" rather than "downstream" can provide for a safer, more effective outcome.
7.  Therapeutic substances that selectively modulate kinase signaling processes associated with inflammation with intermediary and not high potency may be the most effective substances for managing long-term chronic inflammation.
8.  The natural selection process in plants for specific phytochemicals that modulate inflammatory and metabolic regulatory processes in humans may represent the longest-term "research project" for the development of safe and effective modulators of chronic inflammation.
9.  Assessment of inflammation should focus on a patient-centered approach that couples history, physical examination, family history, environmental, lifestyle, and nutritional factors with specific serological tests.

Based in Gig Harbor, Washington, Dr. Jeffrey Bland has been an internationally recognized leader in the nutritional medicine field for over 25 years. Dr. Bland founded HealthComm International, Inc. in 1984, and served as its Chief Executive Officer until a merger with its strategic partner, Metagenics, in 2000. Dr. Bland currently serves at Chief Science Officer for Metagenics and President of MetaProteomics.

A nutritional biochemist and registered clinical laboratory director, Dr. Bland is a former professor of biochemistry at the University of Puget Sound, and a previous Director of Nutritional Research at the Linus Pauling Institute of Science and Medicine. He is one of the four original founders of Bastyr University, the first federally accredited university in the United States offering graduate and undergraduate degrees in natural medicine. With his wife, Susan Bland, MA, he founded the Institute for Functional Medicine, now a respected nonprofit organization.

Notes
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