Inflammation: the key to health and disease.

Nagarkatti, Prakash ; DiPette, Donald J.

INTRODUCTION

Recently, National Institutes of Health (NIH) awarded a 5 year $ 6 million grant to the University of South Carolina (USC) to establish a Center of Excellence for Complementary and Alternative Medicine Research on Autoimmune and Inflammatory Disease. The University of California Los Angeles and the Mount Sinai School of Medicine were the only other institutions awarded centers in 2007. Previously centers have been awarded at Harvard Medical School, Massachusetts General Hospital, Oregon State and Temple universities, and the universities of Maryland, North Carolina and California-San Francisco. The underlying focus of the NIH Center at USC is to study the mechanisms by which plant products suppress inflammation so that they can be used as preventive or therapeutic modalities against autoimmune diseases (http://camcenter.med.sc.edu/). The goal of this review is to provide an understanding of inflammation, discuss its role in health and disease, and provide an overview of how the NIH Center award and research in inflammation at the USC School of Medicine (SOM) provides the niche to bring together many research focus areas in basic and clinical sciences by providing a platform for multidisciplinary collaborations and research advancement.

Inflammation which is defined clinically as heat, pain, redness, and edema, actually results from a physiological response to tissue injury and infection (Oke and Tracey, 2007). Inflammation is a double-edged sword--while it is critical in restoring tissue homeostasis following damage secondary to invading pathogens, foreign bodies, and trauma, inflammation can also trigger acute and chronic diseases. This list includes major pathological disorders such as autoimmune diseases, allergies, cardiovascular diseases, neurodegenerative diseases and cancer. Thus, inflammation plays a critical role in the pathogenesis of a wide range of diseases.

Inflammation can be classified as either acute or chronic. During acute inflammation, the body responds to harmful stimuli through movement of plasma and the white blood cells of the immune system, called leukocytes, from the blood into the injured tissues. Acute inflammation plays a critical role in clearing infections and in tissue healing. If the inflammation persists for prolonged periods, it is known as chronic inflammation. This can lead to a progressive shift in the nature of immune cells that are present at the site of inflammation and can trigger tissue destruction, injury and organ failure. During inflammation, the cells of the immune system release a large number of chemical mediators known as chemokines and cytokines. Some of the important cytokine mediators include interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and interferon gamma (IFN). In the early stages of inflammation, the predominant cell type infiltrating the tissues is the neutrophil. In contrast, accumulation and activation of macrophages is the hall mark of chronic inflammation. In addition, lymphocytes also contribute towards the development of inflammation by producing cytokines and chemokines.

Autoimmune diseases are disorders in which the immune system, for reasons that are not clear, starts destroying an individuals own cells, tissues or organs by triggering inflammation. These diseases include more than 80 serious, chronic illnesses that involve almost every human organ system. Collectively, they affect 15-20 million people in the USA. They are more common in women and are considered to be among the 10 leading causes of death in women in the US under the age of 65 years. Currently, there is no known cure for autoimmune diseases. Prominent examples of these diseases include Coeliac disease, diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE), Sjogren's syndrome, multiple sclerosis (MS), Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, myesthenia gravis and rheumatoid arthritis (RA).

The main objective of newly funded NIH Center at USC is to conduct research that would determine whether various plant-derived compounds possess immunosuppressive activity and to determine their efficacy against autoimmune diseases. Initially, the NIH Center will pursue three projects. Project one, led by Dr. Prakash Nagarkatti from the USC SOM, will investigate the effect of resveratrol (trans-3,5,4'-trihydroxystilbene) on experimental allergic encephalomyelitis (EAE), a model for human MS. Resveratrol, a polyphenolic compound found in plant products including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Recently, we demonstrated that resveratrol treatment decreased the clinical symptoms and inflammatory responses in an experimental MS model (Singh et al., 2007). Resveratrol was shown to act through the Aryl Hydrocarbon receptor (AhR) and estrogen receptors (ER) found on immune cells which, in turn, triggered apoptosis (programmed cell death) in these cells. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines including TNF-alpha, interferon-gamma, and the interleukins (IL)-2, IL-9, IL-12, IL-17, for instance (Singh et al., 2007). These studies suggest that resveratrol and other plant-derived products may be benefiscial in the treatment of not only autoimmune diseases but also other inflammatory disorders as well. Project two, led by Dr. Mitzi Nagarkatti, will investigate the effect of compounds isolated from hemp oil on the suppression of the immune response which may be beneficial in the treatment of autoimmune hepatitis. Project three, led by Dr. Lorne Hofseth from the USC College of Pharmacy will test the efficacy of American ginseng on colitis and colon cancer. Preliminary studies suggest that ginseng is very effective in suppressing colitis and development of colon cancer in an experimental model. The Center will also provide core resource facilities, which will enable, the screening of the potential toxic effects of plant-derived compounds on the immune system. These facilities will be led by Drs Narendra Singh and Robert Price from the USC SOM. The Center will also create training opportunities for new investigators to pursue research on CAM and establish the basis upon which to initiate clinical trials on compounds that exhibit efficacy against specific autoimmune diseases.

While the USC School of Medicine has many areas of research strengths, three specific research areas have been identified for further development. These areas include cancer, cardiovascular diseases and neuroscience. It is interesting to note that inflammation is a common thread that weaves throughout the pathogenesis of diseases represented in these areas.

INFLAMMATION AND CANCER

Although inflammation is a necessary response to clear infections and to repair tissue injury, chronic inflammation has been shown to correlate an increased risk of developing cancer. Recent studies have revealed that inflammation is a critical component of tumor progression (Coussens and Werb, 2002). Inflammation functions at all three stages of tumor development: initiation, progression and metastasis. Inflammation contributes to the initiation of cancer by triggering the release of a variety of cytokines and chemokines which in turn cause oxidative damage, DNA mutations, and other changes in the microenvironment. Such changes make it more conducive for cell transformation and the increased survival and proliferation of tumor cells. Such novel insights are leading to the use of anti-inflammatory agents as therapeutic approaches to prevent cancer development and progression. The recognition of the importance of inflammation to oncogenesis has led to clinical trials investigating the use of anti-inflammatory drugs, such as COX-2 specific inhibitors for cancer prophylaxis and treatment. A NIH think tank on cancer biology has recently dealt with this topic at length

(http://dcb.nci.nih.gov/thinktank/Executive_Summary_of_Inflammation _and_Cancer_Think_Tank.cfm).

CARDIOVASCULAR DISEASES AND INFLAMMATION

It is becoming increasingly clear that inflammation of blood vessels is one of the major factors that increase the incidence of cardiovascular diseases, including atherosclerosis, hypertension, stroke and myocardial infarction or heart attack. Initiation and progression of vascular inflammation is a complex process involving macrophages of the immune system. The proinflammatory mediators produced by macrophages increase tissue oxidative stress and lipid retention, which participate directly in vascular remodeling (Yan and Hansson, 2007). Normally, endothelial cells (ECs), which line the blood vessel, resist adhesion by leukocytes. However, triggers of atherosclerosis, such as consuming a high-saturated-fat diet, smoking, hypertension, hyperglycemia, obesity, or insulin resistance, can initiate the expression of adhesion molecules by ECs, thus allowing the attachment of leukocytes to the arterial wall (Libby, 2006). After adhering to the endothelium, blood monocytes penetrate the endothelial lining and mature into macrophages, and engulf modified lipoproteins. Cholesterol esters accumulate in the cytoplasm, and the macrophages become foam cells through lipid uptake which characterizes the early stages of atherosclerosis. Also, the macrophages multiply and release several growth factors and cytokines, thereby amplifying and sustaining proinflammatory mediators (Libby, 2006). Thus, inflammation is central to the progression from fatty streak to complex plaque. Recent studies suggest that drugs commonly prescribed to lower cholesterol such as statins also reduce inflammation, suggesting an additional beneficial effect of such drugs.

Similar inflammatory tissue processes are also involved in the pathogenesis of hypertension. It is becoming increasingly clear that known mediators that increase blood pressure, such as angiotensin-II, also increase oxidative stress and inflammation both of which contributes to the target organ damage to the heart, brain, kidney, and blood vessels secondary to the hypertensive process. Our laboratory has recently demonstrated that certain endogenous neuropeptides, such as calcitonin gene-related peptide, improve hypertension by vasodilation and inhibiting oxidative stress and inflammation (Bowers et al., 2005). These studies provide an opportunity for the development of new pharmacologic targets to treat hypertension and its deadly consequences.

INFLAMMATION AND NEURODEGENERATIVE DISEASES:

There is growing evidence that links immune system and the CNS. For example, various immune cells can traverse the blood-brain barrier. During the development of the CNS, blood monocytes populate the brain to differentiate into microglia. Invading lymphocytes can attack target antigens in the CNS such as during MS or produce growth factors that might protect neurons against degeneration. Immune molecules, such as interleukins and chemokines, are also expressed at high levels in neurons and may be involved in the communication of neurons with glial cells. Moreover, the inflammatory reflex is a neurophysiological mechanism that regulates the immune system (Oke and Tracey, 2007). The efferent branch of the reflex include the cholinergic antiinflammatory pathway involving the vagus nerve, which inhibits inflammation by suppressing cytokine synthesis through the release of acetylcholine in immune organs, the liver, and the gastrointestinal tract. Thus, such a neurological control mechanism regulates inflammation via acetylcholine and suppresses production of proinflammatory cytokines (Oke and Tracey, 2007).

Inflammation during neurodegenerative disorders can be triggered by a number of causes including protein aggregates, molecules released from or associated with injured neurons or synapses, and dysregulation in the mechanisms that control inflammation. The resulting inflammatory responses may modulate neurodegenerative pathways with a potential beneficial or detrimental effect. Emerging evidence suggests that inflammation may account for chronic neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Creutzfeldt-Jakob disease (Minghetti, 2005). In these diseases, inflammation is atypical and occurs in the absence of robust leucocyte infiltration. In these diseases, resident microglia which are the macrophages of brain parenchyma appear to play a major role. In healthy normal brain, microglia are present in an inactive phase as compared with other tissue macrophages, but subtle microenvironmental changes can induce microglia to react rapidly, change morphology and acquire an array of functions, including phagocytosis and secretion of inflammatory mediators. In addition to microglia, reactive astrocytes contribute to the process by restricting the area of lesion and releasing local mediators. This localized process, is distinct from inflammation seen in other tissues and is often referred to as 'neuroinflammation' (Minghetti, 2005). This unique neuroinflammation is a doubleedged sword which is both neuroprotective as well as can trigger neurodegenerative disorders (Minghetti, 2005). Thus, understanding the dynamic relationship between beneficial and detrimental effects of neuroinflammation is central to the prevention and treatment of neurodegenerative diseases.

TREATMENT OF INFLAMMATION

Historically, anti-inflammatory drugs were discovered when certain plants and their extracts were found to relieve pain, fever and inflammation (Rainsford, 2007). Salicylates were discovered in the mid-19th century from Willow and this enabled the synthesis of acetyl-salicylic acid leading to development of Aspirin. Subsequent research in 19th-20th centuries led to the development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were developed. The major adverse effects associated with NSAIDS were the associated gastro-intestinal (GI) toxicity. In the 1990's two cyclo-oxygenase (COX) enzyme systems controlling the production of prostaglandins (PGs) and thromboxane (TxA2) were discovered. COX-1 produces PGs and TxA2 which play a role in gastrointestinal, renal, and vascular functions, and COX-2 produces PGs which are involved in inflammation, pain and fever. This led to the discovery of inhibitors of the COX enzymes. While COX-2 inhibitors were enthusiastically received due to their low GI side effects, there are recent concerns regarding an increase in cardiovascular toxicity of these agents. Because inflammation plays a crucial role in the pathogenesis of a wide range of diseases including autoimmune diseases, allergies, cancer, cardiovascular diseases and neurodegenerative diseases as discussed above, one can imagine how crucial it is to discover new anti-inflammatory drugs, and the potential impact such discoveries will have on human health and disease.

CONCLUDING REMARKS:

Inflammation is a process that enables the host to fight and overcome infections, cancer and help repair damaged tissues. Interestingly, however, inflammation has become one of the hottest areas of medical research because it also plays a significant role in the pathogenesis of a large number of human diseases, including autoimmune diseases, allergies, cardiovascular diseases, neurodegenerative diseases and cancer. It is indeed distressing that despite extensive research, highly effective treatment modalities do not exist to treat inflammation. The concept that inflammation contributes to the underlying cause of such varied diseases is so intriguing because it suggests the possibility to treat major human ailments through a single inflammation-reducing agent. Thus, it is not surprising that the NIH in its new roadmap initiatives for 2008 has identified inflammation as one of the key topics. The NIH website (http://nihroadmap.nih.gov/2008initiatives.asp) states, "While significant breakthroughs have occurred in our understanding of inflammation, research is needed to further understand inflammatory processes. Because inflammation is broadly implicated in many diseases and conditions, this initiative would be valuable in uncovering as-yet-unknown immune mechanisms and mediators of inflammation as well as genetic factors, environmental triggers, and the relationship of inflammation to disease".

The USC SOM is excited about the recognition of its research efforts afforded by the NIH to initiate and develop the Center for Autoimmune and Inflammatory diseases with the research focus on inflammation, and we believe that this initiative provides us with the niche not only to advance research on inflammation but also extend it to other areas of research including cancer, cardiovascular diseases and neurodegenerative disorder.

LITERATURE CITED

Bowers, M, Katki, K, Rao, A, Koehler, M, Patel, P, Spiekerman, A, DiPette, D.J, Supowit, S.C. Role of Calcitonin Gene-Related Peptide in Hypertension-Induced Renal Damage. Hypertension , 45:109-114, 2005.

Coussens, L. M. and Werb, Z. Inflammation and cancer. Nature, 420: 860-867, 2002.

Libby, P. Inflammation and cardiovascular disease mechanisms. American Journal of Clinical Nutrition, 83: 456S-460S, 2006.

Minghetti, L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol, 18: 315-321, 2005.

Oke, S. L. and Tracey, K. J. From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex. J Leukoc Biol, 2007.Rainsford, K. D. Anti-inflammatory drugs in the 21st century. Subcell Biochem, 42: 3-27, 2007.

Singh, N. P., Hegde, V. L., Hofseth, L. J., Nagarkatti, M., and Nagarkatti, P. Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol Pharmacol, 72: 1508-1521, 2007.

Yan ZQ, Hansson GK. 2007. Innate immunity, macrophage activation, and atherosclerosis. Immunology Review. 219: 187-203.

Prakash Nagarkatti Ph. D. * and Donald J. DiPette M. D.

University of South Carolina School of Medicine, Columbia, SC

* Dr. Prakash Nagarkatti, Associate Dean for Basic Sciences, Health Sciences Distinguished Professor, Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine pnagark@gw.med.sc.edu