Pic Chronic Infla
Pic Chronic Infla
Pic Chronic Infla
REVIEW
Introduction
Inflammation is a normal biological process in response to tissue
injury, microbial pathogen infection and chemical irritation. This
biological process also involves the innate and adaptive immune
systems. At a damaged site, inflammation is initiated by migration of immune cells from blood vessels and release of mediators,
followed by recruitment of inflammatory cells and release of
reactive oxygen species (ROS), reactive nitrogen species (RNS)
and proinflammatory cytokines to eliminate foreign pathogens,
resolving infection and repairing injured tissues.1,2 Thus, the
main function of inflammation is beneficial for a hosts defense.
In general, normal inflammation is rapid and self-limiting, but
aberrant resolution and prolonged inflammation causes various
chronic disorders.3
Chronic inflammation can inflict more serious damage to
a host tissue than bacterial infection. Diverse ROS and RNS such
as O2 (superoxide anion), OH (hydroxyl radical), H2O2
(hydrogen peroxide), nitric oxide (NO), and 1O2 (singlet oxygen)
generated by inflammatory cells injure cellular biomolecules
including nucleic acids, proteins and lipids, causing cellular and
tissue damage, which in turn augments the state of inflammation.4 These also trigger a series of signaling molecules, inflammatory gene expression and activation of enzymes involved in
chronic inflammation. Inflammatory chemicals produced by
inflamed and immune cells also attack normal tissues
surrounding the infected tissue, causing oxidative damage and
extensive tissue inflammation.1,4
a
Department of Seafood Science, National Kaohsiung Marine University,
No.142, Haijhuan Rd., Nanzih District, Kaohsiung, 81143, Taiwan.
E-mail: mhpan@mail.nkmu.edu.tw; Fax: (+886)-7-361-1261; Tel:
(+886)-7-361-7141 Ext 3623
b
Department of Food Science, Rutgers University, 65 Dudley Road, New
Brunswick, New Jersey, 08901-8520, USA. E-mail: ho@aesop.rutgers.
edu; Fax: +1-732-932-6776
such as monocyte chemoattractant protein-1 (MCP-1), proinflammatory cytokines (TNF-a and ILs) as well as growth factors
(PDGF and TGF-b) produced by activated T cells and macrophage.11 Among these, studies indicate that MCP-1 is important
for recruitment of monocytes into intima. Differentiated macrophages that expresse scavenger receptors become foam cells via
uptake of ox-LDL generated in the intima resulting in formation
of fatty streaks.12 The molecules secreted by monocytes, macrophages and arterial cells maintain an inflammatory response
within the artery and promote proliferation and migration of
vascular smooth muscle cells.9,11 Proliferative smooth muscle cells
release fibrogenic mediators and build a dense extracellular matrix
around foam cells and monocytes, finally causingfatty streaks to
progress into fibrous plaque.13
In pathogenesis and progression of atherosclerosis, chronic
inflammation is involved in every stage that is characterized by
infiltration of monocytes/macrophages and production of
proinflammatory cytokines9,11 (Fig. 2). Hence, the modulation or
regulation of the interaction between endothelial and inflammatory cells and the transformation of macrophages to foam
cells could be the basis for the beneficial effects that prevent or
slow down the progression of this disease. This diversity of
cytokine expression and function might also lead to the identification of selective therapeutic targets for the prevention and
treatment of atherosclerosis.10,11
Moreover, clinical research shows that elevated levels of
systemic inflammatory molecules including IL-6, ICAM-1,
P-selectin, E-selectin and C-reactive protein (CRP), are classic
acute-phase markers occurring in patients with coronary disease,
and, therefore that might be a predictor of cardiovascular
risk.14,15 Different treatments of atherosclerosis are associated
with reduction of these inflammatory markers, providing a new
target for blockage or therapy of atherosclerosis by inhibition of
inflammation.9,16
This journal is The Royal Society of Chemistry 2010
Neurological disorders
Fig. 3 Neuroinflammation in Alzheimers disease. During the development of Alzheimers disease, b amyloid peptide is produced by cleavage of
amyloid precursor protein (APP), aggregates and accumulates as b amyloid plaques. Both aggregates and plaques cause neurotoxicity or activation of
microglia through up-regulating NF-kB and AP-1 transcription factors, which in turn release ROS and pro-inflammatory cytokines such as NO, PGE2,
IL-1, IL-6, and TNF-a that damage cholinergic neuron. These pro-inflammatory cytokines also directly activate astrocytes that also produce cytokines
to amplify inflammatory signals and result in neuroinflammation and neurodegeneration. Flavonoids act through avoiding b amyloid induced-neuron
injury and death, modulation of pro-inflammatory cytokines and ROS production as well as inhibiting the activation of microglia and astrocyte as
neuroprotective mechanisms.
In recent years, many studies document that obesity is significantly associated with a chronic low-grade inflammation29
(Fig. 4). The first connection between obesity and inflammation
is evidenced by the release of TNF-a from adipocytes. As the
lipid content increases in adipose tissue, adipocytes synthesize
TNF-a and several cytokines (IL-1b and IL-6) that change the
number and size of cells, influencing lipoprotein lipase and
increasing the inflammatory state.30 TNF-a also induces insulin
resistance by downregulation of insulin receptor phosphorylation, decrease of glucose uptake and expression of GLUT4
transporter.29,31 Another important inflammatory feature in
adipose tissue is recruitment of immune and inflammatory cells
such as neutrophils, eosinophils and macrophages.32 Studies in
both mice and humans show that while in an obese state,
macrophage infiltration is increased in adipose tissue.32 Large
adipocytes secret chemotactic signals, such as monocyte chemoattractant protein-1 (MCP-1), to trigger infiltration of
macrophages, that then leads to the creation of a chronic, lowgrade inflammation in obesity.32,33 Increased levels of acute phase
protein CRP are found in many obese individuals,34 and circulating CRP concentrations are related to the development of
cardiovascular disease,14 indicating the association of obesity
and cardiovascular disease. Some lines of evidence also suggest
that obesity is linked to fat storage in the liver that can lead to the
development of fatty liver diseases.25 It is suggested that IL-6
derived from adipocytes may drive the production of CRP in the
liver.35 Overexpression of MCP-1 in adipose tissue leads to
increase of hepatic triglyceride content.33 In addition, elevated
levels of circulating TNF-a in an obese state is often associated
with an increase in insulin resistance.31,36 These observations
emphasize the correlation among obesity, inflammation and
metabolic disorders.
Fig. 4 Obesity in the induction of inflammation. Adipose tissue of visceral obesity induced chronic low-grade inflammation through macrophage
infiltration by MCP-1 and secretion of pro-inflammatory factors. However, obesity may cause the high risk in development of several diseases.
Metabolic disorders
Extensive research reveals that inflammation is a characteristic
feature of metabolic disorders, including fatty liver disease, type
2 diabetes, chronic kidney disease and heart disease (Fig. 5).
Inflammatory responses are considered to be a critical stage of
metabolic dysfunction characterized by abnormal proinflammatory cytokine production, increased acute phase protein
and activation of inflammatory signaling pathways.37 In addition, obesity correlates with an increase in inflammatory conditions and metabolic syndromes.29 Type 2 diabetes is the most
prevalent and serious metabolic disease caused by insulin resistance derived from pancreatic beta cell dysfunction. Both
experimental and clinical studies demonstrate that several
inflammatory cytokines are closely related to pathogenesis of
insulin resistance.38 Increased levels of IL-1b in plasma are
shown to have detrimental effects on the function of IL-1
receptor antagonist proteins (IL-1ra) that promote beta cell
destruction and alter insulin sensitivity.39 Moreover, IL-6 acts on
activation of tyrosine phosphatase and interferes with the interaction between insulin receptor and suppressor of cytokine
signaling (SOCS) proteins that result in insulin resistance.40 In
patients with chronic kidney disease, elevated levels of serum
acute phase proteins such as C reactive protein (CRP), TNF-a
and ILs are associated with an increase in chronic inflammatory
states and insulin resistance.41 In addition to insulin resistance
and Type 2 diabetes, an elevated concentration of CRP and
Fig. 5 Proinflammatory cytokines in insulin resistance and metabolic disorders. Insulin synthesized and secreted from b cells in pancreas acts as normal
function in different organs and tissues, includes reducing glucose production and output in liver, facilitating glucose uptake in skeletal muscle, and
decreasing lipolysis in adipose tissue. Excessive pro-inflammatory cytokines (CRP, IL-1, IL-6, and TNF-a) cause dysfunction of b cell or recruit of
inflammatory cells (monocytes and macrophages) that affect both insulin secretion and insulin action, promote pathogenesis of insulin resistance and
subsequently reducing insulin-dependent signalling. This local insulin resistance also contributes to its target tissues such as increase concentration of
glucose and fatty acids in skeletal muscle, liver and adipose tissue that lead to various metabolic disorders. Flavonoids act through interfering with proinflammatory cytokines-induced b cells dysfunction and cell death, decreasing cytokines production, up-regulation of insulin-dependent signaling and
improving glucose uptake in different cell types.
Fig. 6 Mechanisms of inflammation-associated pathogenesis in rheumatoid arthritis and osteoporosis. In inflamed rheumatoid synovium and bone
tissue, pro-inflammatory cytokines produced by recruited inflammatory cells (macrophages, T cells and B cells), endothelial cells and synovial fibroblasts
are central to the inflammatory process in rheumatoid arthritis and osteoporosis. This pathological process also involves in innate and adaptive
immunity responses. These pro-inflammatory cytokines result in activation of synovial fibroblasts and produce proteases that lead to tissue destruction.
In addition, cytokines-trigger activation and differentiation of osteoclasts are important in bone loss. Flavonoids act through reducing recruitment of
inflammatory cells, cytokines production, MMPs expression, and activation or differentiation of osteoclasts.
receptor activator of NF-kB (RANK), activation and differentiation of osteoclast, and decreased osteoblast survival.46 Despite
several in vitro and in vivo studies indicating that proinflammatory cytokines contribute to osteoporosis, and increased
levels of IL-1b, IL-6 and TNF-a in whole blood culture from
patients with osteoporosis, the mechanism involved in bone loss
is still unclear. In addition, recent studies also reveal that elevated
systemic CRP is associated with poor bone health.46,47
Chronic inflammatory diseases
A continued chronic inflammatory state in different organs and
tissues leads to a various chronic inflammatory diseases such as
chronic obstructive pulmonary disease (COPD), psoriasis,
rheumatoid arthritis, chronic pancreatitis and inflammatory
bowel disease (IBD) all of which are frequently associated with
infiltration of immune and inflammatory cells. For example,
inflammatory bowel disease leads to ulcerative colitis (UC) and
Crohns disease (CD), based on clinical features and
This journal is The Royal Society of Chemistry 2010
Fig. 7 Underlying mechanisms in inflammatory bowel disease. As bacteria infection or environmental factors that cause colonic endothelium damage
result in recruitment of inflammatory and immune cells from bloodstream. Accumulated inflammatory cells produce pro-inflammatory mediators that
trigger proliferation and activation of T cells, lead to differentiate to Th1 and Th2 cells that result in amplification of inflammatory cascade and cause
tissue injury. Flavonoids act through decreasing inflammatory cytokines production, reducing recruitment of inflammatory cells and modulation of
differentiation and proliferation of T cells.
Cancers
Several lines of evidence indicate that cancer development in
humans is a multistep and long-term process which requires six
properties, including limitless replication potential, evasion of
apoptosis, self-sufficiency in growth signals, insensitivity to antigrowth signals, sustained angiogenesis, and tissue invasion and
metastasis.51 Since Virchow observed in 18th century, that
cancers frequently occur at sites of chronic irritation, much
research confirms the concept that chronic inflammation is
a critical component of tumor promotion and progression,
including colorectal, gastric, pancreatic, pulmonary, cystic,
hepatocellular, ovarian, skin and esophageal cancers.4,52 In view
of inflammation involved in different cancers, increasing
Food Funct., 2010, 1, 1531 | 21
evidence suggests that inflammation should be the seventh hallmarker in cancer development.53
The pathological mechanism of inflammation involved in
tumorigenesis is very complicated.54 In tissue injury or inflammatory stimulation, inflammatory cells are recruited and
production of pro-inflammatory cytokines and diverse ROS and
RNS that induce genetic change which enhances malignant
transformation and proliferation of initiated cells. Subsequently,
as tumor tissue forms, inflammation continues to promote
development of cancer by creating an inflammatory microenvironment, which consists of stromal cells, inflammatory cells and
the extracellular matrix from surrounding tissues. The inflammatory and immuosuppressive cytokines and chemokines
secreted from these cells not only promotes proliferation,
angiogenesis, invasion and metastasis but also suppresses the
hosts immune system and facilitates tumor growth and development54,55 (Fig. 8).
There are many key molecules that link inflammation and
cancer, including transcription factors, signal transducers and
activators of transcription 3 (STAT3), nuclear factor-kB (NFkB), nuclear factor of activated T-cells (NFAT), activator
protein-1 (AP-1), CCAAT enhancer binding protein (C/EBP),
cAMP response element binding protein/p300 (CBP/p300),
Fig. 8 Role of inflammation in cancer development. Chronic inflammation is a critical component of tumor promotion and progression, including
colorectal, gastric, pancreas, lung, bladder, hepatocellular, ovary, skin and esophageal cancers. In colonic tumorigenesis, inflammatory stimulation,
inflammatory cells are recruited and production of pro-inflammatory cytokines and diverse ROS and RNS that induction of genetic change, enhanced
malignant transformation and proliferation of initiated cells. Subsequently, as tumor tissue formation, inflammation also promotes development of
cancer by creating an inflammatory microenvironment. The inflammatory and immuosuppressive cytokines and chemokines secreted from these cells
not only promote proliferation, angiogenesis, invasion and metastasis but also suppress the hosts immune system and facilitates tumor growth and
development.
Groups
Structure
Examples
Flavones
Flavonols
Flavanols
Catechin, gallocatechin,
epicatechin, epigallocatechin-3gallate
Flavanones
Isoflavones
Anthocyanidins
Cyanidin, delphinidin,
pelargonidin
that relieves the infiltration of eosinophils and airway inflammation in asthmatic rats.78 It is suggested that the inhibition of foam
cells forming macrophage and ox-LDL uptake is one of the targets
for atherosclerosis. Nobiletin inhibited macrophage foam-cell
formation through reducing metabolism of b-VLDL, is primarily
taken up by macrophages via the LDL receptor in cultured murine
J774A.1 macrophages.79 Several studies demonstrate that nobiletin can improve arthritic diseases as evidenced by decreasing
proinflammatory cytokine production in human synovial cells
and downregulating gene expression of MMPs in human synovial
fibroblasts,80 as well as in collagen-induced arthritic (CIA) mice.81
Nobiletin can also inhibit leukocyte infiltration, protein expression of iNOS and COX-2 as well as tumorigenesis in mouse skin.1
In our previous studies, we reported that a metabolite of nobiletin
This journal is The Royal Society of Chemistry 2010
Fig. 9 Representative natural flavonoids and their dietary sources. (A) flavones, (B) flavonols, (C) flavanols, (D) flavanones, (F) isoflavones, (G)
anthocyanidins.
(30 ,40 -didemethylnobiletin) and 5-hydroxy-3,6,7,8,30 ,40 -hexamethoxyflavone, a hydroxylated PMF in citrus peel, inhibited
12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced skin
inflammation and tumor promotion by suppressing MAPK and
PI3K/Akt signaling pathways.82,83
Recently, two new flavones isolated from Cirsium japonicum
DC, pectolinarin and 5,7-dihydroxy-6,40 -dimethoxyflavone were
found to reduce high-carbohydrate/high-fat diet-induced diabetes in rat through decreasing plasma glucose and increasing
adiponectin levels that may improve glucose and lipid homeostasis.84
Flavonols
Quercetin, an ubiquitous plant secondary metabolite, is found
abundant in onions, broccoli, apples, grapes, wine, tea, and leafy
green vegetables, is well known as a potent antioxidant and antiinflammatory agent. Recently, it was shown to possess good antiatherosclerotic activity. In human umbilical vein endothelial cells
(HUVECs), quercetin treatment strongly attenuated the inflammation-induced upregulated expression of VCAM-1, ICAM-1
and monocyte chemoattractant protein-1 (MCP-1), which may
contribute to its interference with the interaction between
monocytes and vascular endothelial cells during the early stages
of atherosclerosis.85 Oral feeding of quercetin (64-mg/kg body
weight daily) significantly inhibited atherosclerotic lesion size in
the aortic sinus and thoracic aorta through reducing superoxide
production, improving endothelial NO synthase (eNOS) function and decreasing plasma-sP-selectin levels in the apolipoprotein E (ApoE)(-/-) gene-knockout mouse.86 Quercetin also
decreased circulating inflammatory markers, including IFNg,
IL-1a and IL-4 in high fat diet animal models and therefore may
improve inflammation or obesity-associated disorder.87 In addition, consumption of quercetin is found to decrease systolic
blood pressure and plasma oxidised LDL in obese subjects (aged
2565 years) without affecting liver and kidney functions.88
When rats were fed a diet of rutin, a quercetin glycoside, there
was markedly attenuated dextran sulfate sodium (DSS) induced
gene expression of IL-1b and IL-6 in colonic mucosa and
decreased intestinal colitis.89 Quercetin was found to inhibit
2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of rats
possibly through downregulation of TNF-a-induced NF-kB
activation.90
Kaempferol, another flavonol-type flavonoid present in broccoli, tea and various vegetables, is considered to improve osteoporosis. For example, treatment with kaempferol stimulated
differentiation and mineralization of murine pre-osteoblastic cell
lines that may contribute to the prevention of bone loss.91 In the
pathology of osteoporosis, proinflammatory cytokines TNF-a is
important for bone disruption and osteoclastogenic cytokine
production. Kaempferol was reported to antagonize TNF-ainduced p65 translocation and production of IL-6 and MCP-1as
well as RANKL-triggered osteoclast precursor cell differentiation. These data indicate that kaempferol exerted a profound
anti-osteoclastogenic effect.92 Advanced glycation end products
(AGE) are oxidative products formed from nonenzymatic reaction of reducing sugars with free amino groups of proteins. AGE
is reported to be involved in diabetic complications and various
age/inflammation-related chronic diseases through generation of
26 | Food Funct., 2010, 1, 1531
Conclusion
Chronic inflammation is linked to numerous human diseases.
Increasingly epidemiological and experimental studies demonstrate that modulation of inflammatory response by natural
phytochemicals plays an important role in the prevention, mitigation, and treatment of many chronic inflammatory diseases.
Flavonoids are a group of natural compounds widely present in
vegetables, fruits and edible plants that possess potent biological
activities. Dietary intake of flavonoids is suggested to prevent
and lower the risk of chronic diseases. In this review, we discussed the possible mechanisms by which flavonoids play a role
in the regulation of the inflammatory processes associated with
atherosclerosis (cardiovascular disease), neurodegenerative
diseases, obesity, metabolic disorders, bone, muscular and skeletal diseases, and chronic inflammatory diseases, as well as
cancers. The anti-inflammatory activity of flavonoids is seen
through several mechanisms involving the modulation of
inflammatory signaling, reduction of inflammatory molecule
production, diminishing recruitment and activation of
inflammatory cells, regulation of cellular function and their
This journal is The Royal Society of Chemistry 2010
antioxidative property. Regarding the safety, ability and the antiinflammatory effects of flavonoids, they are likely to have
a potential role in preventive and therapeutic roles in chronic
inflammatory conditions. However, additional, extensive
research of flavonoids in strengthening the network of inflammatory response needs to be studied in the future.
Abbreviations
Ab
AGE
AP-1
ApoE
APP
a-SMA
ATF
CBP/p300
CD
C/EBP
c-FLIP
CIA
COPD
COX-2
CRP
CVD
DSS
EC
ECG
EGC
EGCG
ERK1/2
eNOS
GLUT4
GSK-3b
HC gp-39
HDL
HIF-1a
H2O2
HUVEC
ICAM-1
IL
IL-1ra
IBD
IFN-g
IKK
iNOS
IRS-1
JNK
5-LOX
LPS
MAPK
MCP-1
MMP
MPO
MPTP
mTOR
NADPH
oxidase
amyloid b peptide
advanced glycation end products
activator protein-1
apolipoprotein E
amyloid precursor protein
a-smooth muscle actin
activator transcription factor
cAMP response element binding protein/p300
Crohns disease
CCAAT enhancer binding protein
cellular FLICE-like inhibitory protein
collagen-induced arthritic
chronic obstructive pulmonary disease
cyclooxygenase-2
c-active protein
cardiovascular disease
dextran sulfate sodium
epicatechin
epicatechin-3-gallate
epigallocatechin
epigallocatechin-3-gallate
external signal regulated kinase 1/2
endothelial NO synthase
glucose transporter type 4
glycogen synthase kinase 3b
human cartilage glycoprotein-39
high-density lipoprotein
hypoxia inducible factor-1a
hydrogen peroxide
human umbilical vein endothelial cell
intercellular adhesion molecule-1
Interleukin
IL-1 receptor antagonist protein
inflammatory bowel disease
interferon-g
IkB kinase
inducible nitric oxide synthase
insulin receptor substrate-1
c-Jun N-terminal kinase
5-lipoxygenase
lipopolysaccharides
mitogen-activated protein kinase
monocyte chemoattractant protein-1
matrix metalloproteinase
myeloperoxidase
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
mammalian target of rapamycin
nicotinamide adenine dinucleotide phosphateoxidase
NAFLD
NF-ATc1
NF-kB
NFAT
NIK
NO
NSAID
1O2
O2
OH
ox-LDL
p70S6K
PDGF
PGE2
PI3K
pIRS-1
PKC
PPARg
RA
RANKL
ROS
SOCS
STAT
TGF-b
Th cell
TNBS
TNF-a
TPA
UC
VCAM-1
VEGF
VLDL
VSMC
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