Immunonutrition: Interactions of Diet, Genetics, and Inflammation

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Edited by

Bharat B. Aggarwal • David Heber

Interactions of Diet, Genetics, and Inflammation

Aggarwal • Heber

Immunonutrition

Immunonutrition

Immunonutrition

Interactions of Diet,

Genetics, and Inflammation

The interaction of immune function and nutrition underlies the low-grade

chronic inflammation involved in the etiology of many common obesity￾associated and age-related chronic disease conditions. This close interaction

is the genesis of the term immunonutrition, which represents a new

interdisciplinary field of nutritional and medical research. Immunonutrition:

Interactions of Diet, Genetics, and Inflammation introduces the breadth

of this field, which implicates nutrition in both immune function and in the

etiology, prevention, and treatment of common diseases influenced by

inflammation and immune imbalance, including obesity, diabetes, heart

disease, asthma, autoimmune diseases, and common forms of cancer .

The book begins by reviewing the basic mechanisms of immunity and cellular

mechanisms of cytokine activation. It discusses the effects of dietary fat

intake and changes in Western diet and lifestyle linked to inflammation. It

also describes the interaction of genetics and environment in the modulation

of immune function and inflammation and addresses exercise and skeletal

muscle as an endocrine and immune organ. The book reviews the entire

spectrum of inflammation and cancer from causation to its role in tumor

therapy. It examines abdominal obesity and metabolic diseases, interactions

between nutrition and autoimmunity in systemic lupus erythematosus and

rheumatoid arthritis, and inflammation associated with type 2 diabetes,

heart disease, kidney disease, Alzheimer’s disease, and asthma.

Considering potential nutrition-based treatments, the book explores approaches

for reducing abdominal obesity, anti-inflammatory effects of phytochemicals,

practical strategies for increasing fruit and vegetable intake, and anti￾inflammatory properties of spice phytonutrients. In addition, it explores how

uninformed food choices related to fats and oils create a balance of tissue￾selective signals that produce harmful health outcomes and how to restore a

healthy balance.

Immunonutrition

Interactions

of Diet, Genetics,

and Inflammation

Immunonutrition

Interactions

of Diet, Genetics,

and Inflammation

Edited by

Bharat B. Aggarwal

The University of Texas

Houston, Texas, USA

David Heber

UCLA Center for Human Nutrition

Los Angeles, California, USA

Boca Raton London New York

CRC Press is an imprint of the

Taylor & Francis Group, an informa business

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v

Contents

Preface......................................................................................................................vii

Editors.......................................................................................................................ix

Contributors ..............................................................................................................xi

Chapter 1 Evolution of Innate and Adaptive Immunity........................................1

David Heber and Bharat B. Aggarwal

Chapter 2 Cellular Mechanisms of Cytokine Activation.................................... 19

David Heber and Bharat B. Aggarwal

Chapter 3 Cellular Lipids and Inflammation ......................................................39

David Heber and Susanne Henning

Chapter 4 Biomarkers of Inflammation and the Western Diet ........................... 53

David Heber and Susanne Henning

Chapter 5 Phytochemicals and Immune Function.............................................. 67

David Heber

Chapter 6 Genetic and Environmental Modifiers of Immune Function.............85

David Heber

Chapter 7 Cancer and Inflammation................................................................. 101

David Heber

Chapter 8 Abdominal Obesity: Pathophysiology and Related Metabolic

Complications................................................................................... 115

Ana F.T.A. Junqueria and Caroline M. Apovian

Chapter 9 Type 2 Diabetes and Inflammation .................................................. 141

Zhaoping Li and David Heber

vi Contents

Chapter 10 Heart Disease and Inflammation...................................................... 149

Kaveh Daniel Navab

Chapter 11 Chronic Kidney Disease and Inflammation..................................... 167

Karl J. Neff and Carel Le Roux

Chapter 12 Alzheimer’s Disease and Inflammation ........................................... 181

Stephen T. Chen and Gary W. Small

Chapter 13 Nutrition in Autoimmunity: A Focus on Systemic Lupus

Erythematosus and Rheumatoid Arthritis ....................................... 211

Maureen McMahon

Chapter 14 Asthma and Inflammation................................................................229

Andre Nel and David Heber

Chapter 15 Muscle and Immune Function..........................................................245

Anthony Thomas and David Heber

Chapter 16 Approaches to Reducing Abdominal Obesity..................................259

Zhaoping Li and David Heber

Chapter 17 Barriers to Fruit and Vegetable Consumption and Practical

Strategies for Increasing Fruit and Vegetable Intake ....................... 279

Susan Bowerman

Chapter 18 Healthy Fats and Oils: Balancing Omega-3 and

Omega-6 Acids in Tissues................................................................ 291

Bill Lands

Chapter 19 Spices and Dietary Supplements with

Anti-Inflammatory Activity.......................................................... 317

Bharat B. Aggarwal and David Heber

vii

Preface

Immune function and nutrition are closely intertwined in human health. The immune

system is composed of an innate immune system and an adaptive immune system.

The latter is only found in vertebrates while the former is an ancient system that goes

back in evolution to insects and plants.

It is the innate immune system that is overactivated in response to the Western

diet and obesity-associated diseases due to chronic low-grade inflammation. These

diseases range from type 2 diabetes to heart disease, which are closely aligned with

the accumulation of visceral and liver fat resulting in insulin resistance. Individuals

who are about 30 lb overweight or have a body mass index (BMI) of 30 or more

have a 30-fold increased risk of type 2 diabetes mellitus. This 3000% increased risk

is not simply another risk factor but an intrinsic part of the pathogenesis of diabetes

bringing us to call this condition diabesity. However, the etiology of diabetes is not

simply linked to weight but to visceral fat. Individuals in India and China can accu￾mulate visceral fat at normal or even low BMI. Some 70 million Americans have

high blood sugar or prediabetes, and the syndrome, called metabolic syndrome,

affects 50% of individuals between the ages of 50 and 65 in the United States and

many other countries.

The interaction of immune function and nutrition underlies the low-grade chronic

inflammation involved in the etiology of many of the common age-related chronic

disease conditions covered in this textbook. The largest portion of the immune sys￾tem is located adjacent to the gastrointestinal tract. Plants, which also have an innate

immune system, live in soil that is made up of both friendly and potentially toxic

bacteria. Plant roots attract helpful bacteria and repel those bacteria that could attack

them. Humans carry their soil with them in the form of trillions of gut bacteria,

which interact with the immune system. Both dietary intake and obesity influence

the gut microflora, called the microbiome. Plants affect the local bacteria in the soil;

it is thus not surprising that dietary phytochemicals and prebiotics in the human diet

also affect gut microflora.

Diet and exercise are necessary strategies in efforts to reduce visceral fat and

modulate systemic immune function through increased intakes of fruits, vegeta￾bles, plant protein, fish oils, prebiotic fibers, and spices. Nutrition in the broadest

sense determines the health of the immune system. When malnutrition results in

death, it is most commonly caused by infections due to loss of immune function.

Therefore, both in obesity and malnutrition, nutritional factors influence immune

function. This close interaction is the genesis of the term immunonutrition, which

represents a new interdisciplinary field of nutritional and medical research.

It is our hope that this textbook will stimulate increased interest in this new inter￾disciplinary field among students and junior investigators who will carry this field

into the future. There is a need for more human studies to complement the exciting

viii Preface

basic research already developed in cell culture and animal models demonstrating

the mechanisms underlying the interaction of nutrition and immune function. We

hope that this book will achieve these objectives.

David Heber MD, PhD, FACP, FACN

Los Angeles, California

Bharat B. Aggarwal, PhD

Houston, Texas

ix

Editors

David Heber, MD, PhD, FACP, FACN, is the direc￾tor of the UCLA Center for Human Nutrition at the

University of California, Los Angeles. He has been

on the faculty of the UCLA School of Medicine

since 1978 and is currently professor of medicine

and public health. Dr. Heber is board certified in

internal medicine and endocrinology and metabo￾lism by the American Board of Internal Medicine

and is certified as a physician nutrition specialist. He

is a former chair of the Medical Nutrition Council

of the American Society of Nutrition. He directed

both the NCI-funded Clinical Nutrition Research Unit and the NIH Nutrition and

Obesity Training Grants at UCLA. He has written over 230 peer-reviewed scientific

articles and 60 book chapters, as well as three professional texts. He has written four

books for the public, including What Color Is Your Diet? (Harper Collins/Regan

Books, 2001) and the L.A. Shape Diet (Harper Collins/Regan Books, 2004). His

main research interests are obesity prevention and treatment and phytonutrients in

cancer prevention and treatment.

Dr. Bharat B. Aggarwal is a Ransom Horne,

Jr. Distinguished Professor of Cancer Research,

Professor of Cancer Medicine, Professor of

Immunology, Professor of Biochemistry, and

Professor of Experimental Therapeutics, as well

as Chief, Cytokine Research Section, in the

Department of Experimental Therapeutics at the

University of Texas MD Anderson Cancer Center

(MDACC), Houston, Texas. He also serves as a

member of the University of Texas Graduate School

of Biomedical Sciences, Houston; as an adjunct

professor at Albert B. Alkek Institute of Biosciences and Technology, Texas A&M

University, Houston, Texas; and as a member in various institutional committees

of MDACC.

Dr. Aggarwal earned his PhD in biochemistry from the University of California,

Berkeley, and received his postdoctoral training from the Hormone Research

Laboratory at the University of California Medical Center, San Francisco. He

then started his career with Genentech Inc., where he worked for almost 10 years.

His work led to the discovery of TNF-α and TNF-β, essential components of the

immune system, and to the identification of their receptors.

In 1989, Dr. Aggarwal accepted the position of professor and chief of the

Cytokine Research Section at M. D. Anderson Cancer Center, where he currently

x Editors

holds the Ransom Horne, Jr., Endowed Professorship in Cancer Research. Since

then, he has been investigating the role of inflammatory pathways mediated

through TNF, NF-kappaB, and STAT3 for the prevention and therapy of cancer

and other chronic diseases. While searching for novel and safe anti-inflammatory

agents, his group has identified more than 50 novel compounds from dietary

sources and from traditional medicine that interrupt these cell-signaling pathways.

These agents have been tested in various animal models, and some of them are

now in clinical trials. Dr. Aggarwal has published more than 600 papers in peer￾reviewed international journals (including Science, Nature, Cancer Cell, PNAS,

Journal of Experimental Medicine, Blood, JBC, Cancer Research, and Journal of

Immunology), invited reviews, and book chapters.

Dr. Aggarwal is an inventor/coinventor of over 33 patents. He has been included

in ISI Highly Cited among the most popular authors in the immunology category

since 2001. He has also been listed as one of the top 25 researchers worldwide in the

area of apoptosis. His papers exhibit very high citation index (some exceed 1000).

His overall citation is now at 75,900 with an H-index of 106.

Dr. Aggarwal currently serves as a member of the editorial boards of 24 inter￾national journals. He has previously served as a reviewer for more than 160 jour￾nals, various grant proposals, and of several PhD theses. Dr. Aggarwal has edited

12 books and has served as guest editor for special issues of Biotherapy, Cancer

Letters, and Current Opinion in Pharmacology. He has trained over 80 postdoctoral

fellows and visiting professors from around the world. He has co-organized and

served as a member in many national and international conferences and symposia,

started the International Society of Translational Cancer Research, and has delivered

over 350 lectures/seminars/keynote talks in more than 50 countries.

He has recently authored a book entitled Healing Spices (released in January 2011

by Sterling), which is already a bestseller.

Dr. Aggarwal has received numerous awards, including the following:

• ARTOI Award, Association for Research Integrated Oncology Therapies,

Rome, Italy, 2012

• 2011 James A. Duke Award Excellence in Botanical Literature Award,

American Botanical Council, Anaheim, California, 2012

• World Congress Science Prize from Oxygen Club of California, 2010

• Excellence in Research Award of McCormick Research Institute from the

American Association of Nutrition, 2008

• Outstanding Scientist Award from the American Association of Indian

Scientists in Cancer Research, 2006

• Ranbaxy Award for Outstanding Scientist of the Year, 2004

xi

Contributors

Bharat B. Aggarwal

Department of Experimental

Therapeutics

MD Anderson Cancer Center

The University of Texas

Houston, Texas

Caroline M. Apovian

Section of Endocrinology, Diabetes and

Nutrition

Department of Medicine

Boston Medical Center

School of Medicine

Boston University

Boston, Massachusetts

Susan Bowerman

Department of Medicine

Center for Human Nutrition

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

Stephen T. Chen

Department of Psychiatry and

Biobehavioral Sciences

Division of Geriatric Psychiatry

David Geffen School of Medicine

and

Semel Institute for Neuroscience and

Human Behavior

University of California, Los Angeles

Los Angeles, California

David Heber

Department of Medicine

Center for Human Nutrition

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

Susanne Henning

Department of Medicine

Center for Human Nutrition

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

Ana F.T.A. Junqueria

Section of Endocrinology, Diabetes and

Nutrition

Department of Medicine

Boston Medical Center

Boston, Massachusetts

Bill Lands

American Association for the

Advancement of Science

Washington, DC

and

American Society for Nutrition

Bethesda

and

Society for Free Radical Biology and

Medicine

Indianapolis, Indiana

Carel Le Roux

Diabetes Complications Research Centre

Conway Institute of Biomolecular and

Biomedical Research

University College Dublin

Dublin, Ireland

Zhaoping Li

Department of Medicine

Center for Human Nutrition

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

xii Contributors

Maureen McMahon

Division of Rheumatology

Department of Rheumatology

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

Kaveh Daniel Navab

Department of Anesthesiology

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

Karl J. Neff

Diabetes Complications Research Centre

Conway Institute of Biomolecular and

Biomedical Research

University College Dublin

Dublin, Ireland

Andre Nel

Department of Medicine, Pediatrics and

Public Health

Division of NanoMedicine

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

Gary W. Small

Department of Psychiatry and

Biobehavioral Sciences

Division of Geriatric Psychiatry

David Geffen School of Medicine

and

Semel Institute for Neuroscience and

Human Behavior

University of California, Los Angeles

Los Angeles, California

Anthony Thomas

Larry L. Hillblom Islet Research

Center

David Geffen School of Medicine

University of California, Los Angeles

Los Angeles, California

1

1 Evolution of Innate and

Adaptive Immunity

David Heber and Bharat B. Aggarwal

INTRODUCTION

The human immune system can be divided into two functional entities: the innate

and the adaptive immune systems. The innate immune system appeared early in

evolution prior to the time that plants and animals took separate paths, but the

basic mechanisms of pathogen recognition and activation of the innate immune

response are conserved throughout the evolution of plants and animals includ￾ing humans [1]. Innate immunity is the first line of defense against infectious

microorganisms in humans and relies on germ line–encoded pattern recognition

receptors (PRRs) to recognize pathogen-derived substances [1]. Activation of the

innate immune system through these receptors leads to the expression of a vast

array of antimicrobial effector molecules that attack microorganisms at many

different levels.

The innate immune system has been studied extensively in fruit flies (Drosophila

melanogaster) [2] and even in worms such as Caenorhabditis elegans. These ani￾mals have the same genes as vertebrates, including mice and humans, that encode

intracellular signaling pathways leading to the activation of the transcription fac￾tor nuclear factor-kappa B (NFκB). These gene cassettes encode various proteins

CONTENTS

Introduction................................................................................................................1

Evolution of Innate Immunity....................................................................................5

Innate Immune System in Plants...........................................................................5

Innate Immune System in Humans.......................................................................6

Evolution of Cellular Immunity.................................................................................6

Immunity and Inflammation..................................................................................7

Cellular Immunity .................................................................................................7

Adaptive Immune System..........................................................................................9

Malnutrition and Immune Function......................................................................... 10

Immune Function in Obesity ................................................................................... 11

Macrophage Receptors for Omega-3 Fatty Acids.................................................... 11

Immune Function and Vitamin and Mineral Balance .............................................. 12

Practical Considerations for Modulating Immune Function.................................... 14

References................................................................................................................ 15

2 Immunonutrition: Interactions of Diet, Genetics, and Inflammation

of signaling pathways modulating NFκB activation and inflammation discussed

elsewhere in this textbook. This evolutionary history combined with other evidence

supports the notion that the activation of NFκB is the central signaling pathway of

activation in innate immunity, leading in turn to the transcription of a set of genes

dependent on NFκB [3]. Moreover, this pathway is a universal pathway that leads to

activation in all host defense systems.

The adaptive immune system evolved much later in higher species (see

Figure 1.1).

In contrast to innate immunity, the adaptive immune system generates

antigen-specific receptors, antibodies, and T-cell receptors by somatic cell DNA

rearrangement [4]. These receptors, found only in higher eukaryotes, recognize

specific pathogen-encoded proteins. Mammals have a complex immune response,

which relies on communication between the innate and adaptive arms of the immune

system.

In the human gut, trillions of bacteria live in symbiosis with the host and affect

both host nutrition and immune function. Studies confirm that gut microbiota carry

on a dynamic interaction with the intestinal innate and adaptive immune systems,

affecting different aspects of its development and function. Communication between

the mucosal immune system and endogenous microflora favors mutual growth, sur￾vival, and inflammatory control of the intestinal microbiome [5].

Since humans evolved in equilibrium with plants, insects, and bacteria, the

innate and adaptive immune systems were clearly influenced by the innate immune

Protocells

Prokaryotes

Cyanobacteria

Eubacteria

Archaeobacteria

Protista

Algae

Molds

Amoeba

Flagellates

Fungi

Club fungi

Sac fungi

Bread mold

Plants

Angiosperms

Gymnosperms

Seed producers

Horsetails

Club moss

Ferns

Bryophytes

Animals

*Vertebrates*

Echinoderms

Rotifers Anthropods Annelids

Mollusks

Worms Sponges

Adaptive

immunity

Innate

immunity

Innate

immunity

FIGURE 1.1 Adaptive immune function is a late evolutionary development in vertebrates

while innate immune function can be traced back to the earliest cell types including bacteria.