New Progress in Cytokine Research: Effects on Alzheimer...

BIOTECHNOLOGY, MOLECULAR BIOLOGY AND NANOMEDICINE VOL.1 NO.2 DECEMBER 2013

ISSN: 2330-9318 (Print) ISSN: 2330-9326 (Online) http://www.researchpub.org/journal/bmbn/bmbn.html

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Abstract— Multiple types of mediators and signaling

pathways can trigger inflammatory responses. For example,

interleukins are cytokines which regulate inflammatory

responses and are accountable for the communication

between leukocytes. Other examples are chemokines, small

cytokines promoting chemotaxis, and interferons having

antiviral effects. Additionally, these molecules are

implicated in both innate and adaptive immunity, having

an important physiological role in lymphoid tissue

ontogenesis, organogenesis, vasculogenesis and tissue

repair. We summarize here the progress in cytokine

research with special focus on Alzheimer and

Inflammatory Bowel diseases.

Keywords— cytokines, inflammation, neurodegenerative

diseases, inflammatory bowel disease

I. INTRODUCTION

Multiple types of mediators and signaling pathways can trigger

inflammatory responses. For example, interleukins are

cytokines which regulate inflammatory responses and are

accountable for the communication between leukocytes. Other

examples are chemokines, small cytokines promoting

chemotaxis, and interferons having antiviral effects.

Additionally, these molecules are implicated in both innate and

adaptive immunity, having an important physiological role in

lymphoid tissue ontogenesis, organogenesis, vasculogenesis

and tissue repair.[1-3]

The chronic alteration of these molecules results in the

occurrence of various diseases. Cytokine and chemokine

deregulation can particularly support the onset of diseases

related to chronic inflammation, the production or formation of

tumors and autoimmunity. The importance of examining

multiple systemic chemokines and cytokines lies in the

understanding of the complex mechanism of immunological

changes detected in patients with inflammatory and

autoimmune pathologies.[4] Nevertheless, the assessment of

the significance of cytokine and chemokine modulation in

“Iuliu Hatieganu” University of Medicine and Pharmacy, Department of

Anesthesiology, Victor Babes nr.8, 400012 Cluj-Napoca, Romania. *Correspondence to Adina Hadade (e-mail: [email protected]).

pathological conditions requires knowledge of the

physiological range of these molecules in healthy subjects.

Furthermore, additional evidence suggesting that there are

similar clinical presentations and basic therapeutic algorithms

in the onset of these pathologies in children and adults, bearing

in mind the fact that children are not miniature adults. Even

concerning physiological parameters, the aspects which are

specific to children must be considered in case of disease in

order to assure an early diagnosis and an adequate medical

management. Cytokines and chemokines trigger immune

responses and inflammatory processes and their expression, at

least for some of these molecules, is clearly supposed to vary

with age, as the immune system gradually attains full

maturation.[5-7]

II. THE IMPACT OF CYTOKINES ON INFLAMMATORY PROCESSES

IN ALZHEIMER'S DISEASE

Alzheimer‟ s disease (AD) was first defined by Alois

Alzheimer and it is today the most common cause of dementia

in older people. This disease affects more than 4 million people

in the United States[8-10] About 27 million people are

estimated to be suffering from AD in the world.[11] Together

with the increase in life expectancy, the number of people

suffering from AD is believed to increase three times by

2050.[12]

The initial cause of cell damage and the necrotic cells and

tissues caused by it are fought by inflammation. When it

doesn`t restore tissue health, inflammation turns into a chronic

disease that increasingly injures the neighboring tissue. In such

a situation, tissue damage and restoration progress at the same

time. The slow injury of the surrounding tissue can sometimes

be asymptomatic for many years. This can result in severe

tissue damage.[13] Among the pathological indications of AD

is brain inflammation. Nevertheless, the typical inflammatory

characteristics like swelling, heat and pain, do not occur in the

brain. Thus, it is a matter of chronic and not of acute

inflammation.[14] Among the basic features of chronic

inflamed tissues is the high number of monocytes and tissue

macrophages derived from monocytes, namely microglia cells

in the central nervous system (CNS). The clear inflammation

occurs in pathologically exposed regions of the AD brain, with

higher expression of acute phase proteins and pro-

inflammatory cytokines that are scarcely obvious in the healthy

brain.[15]

New Progress in Cytokine Research: Effects on

Alzheimer and Inflammatory Bowel Disease

Adina Hadade, MD,

http://www.researchpub.org/journal/bmbn/bmbn.html



32

The inflammatory reaction is triggered by microglia, astrocytes

and neurons. The following are strongly produced by activated

cells: inflammatory mediators, namely pro-inflammatory

cytokines, chemokines, macrophage inflammatory proteins,

monocyte chemo-attractant proteins, prostaglandins,

leukotrienes, thromboxanes, coagulation factors, reactive

oxygen species (and other radicals), nitric oxide, complement

factors, proteases, protease inhibitors, pentraxins, and

C-reactive protein.[16]

The intractable nature of the Aβ plaques and tangles is assumed

to stimulate a chronic inflammatory reaction in order to

eliminate this waste. These plaques consist of dystrophic

neurites, activated microglia and reactive astrocytes.[17] The

collection of amyloid fibrils and inflammatory mediators

secreted by microglia and astrocytes determine neuronal

dystrophy. Moreover, chronically activated glia release

exceptionally toxic compounds (reactive oxygen intermediates,

nitric oxide (NO), proteolytic enzymes, complementary factors

or excitatory amino acids) and can kill adjacent neurons.[18]

On the other hand, stress and inflammatory mediators enhance

the production of Alzheimer Amyloid Precursor Protein (APP)

and the amyloidogenic processing of APP in order to trigger the

production of amyloid-β-42 (Aβ-42) peptide. Moreover, this

can restrict the generation of soluble APP fraction which

provides neuronal protection.[19]

In turn, Aβ generates pro-inflammatory cytokine expression in

neuroglia in a vicious cycle, activating the complement cascade,

as well as inducing inflammatory enzyme systems, namely the

inducible nitric oxide synthase (iNOS) and the cyclooxygenase

enzyme (COX)-2.[20] There is proof suggesting that all these

factors can lead, individually or in association with each other,

to neuronal impairment and cell death. Small and nonstructural

proteins, cytokines range between 8,000 to 40,000 daltons in

molecular weight. They were initially called lymphokines and

monokines, indicating their cellular sources, but the term

“cytokine” was later used, as almost all nucleated cells can

synthesize these proteins and get a response from them. There

is no 3D or amino acid sequence motif linking cytokines. In

turn, due to their biological functions, cytokines can be grouped

into different categories. Both immune (T-lymphocytes,

macrophages, natural killer cells), as well as nonimmune cells

(Schwann cells, fibroblasts), secrete cytokines. Cytokines have

various biological effects, stimulating or inhibiting cell

proliferation, cytotoxicity or apoptosis, antiviral activity, cell

growth and differentiation, inflammatory responses and

upregulation of surface protein expression. The control over

T-cell differentiation from undifferentiated cells to T-helper 1

and 2 cells, regulatory T cells and T-helper 17 cells is one of the

major cytokine functions.[21] Some of these regulatory

proteins are interleukines (ILs), interferons (IFNs), colony

stimulating factors (CSFs), tumor necrosis factors (TNFs) and

several growth factors (GFs).[22] There have already been

reports that most of these cytokines are produced by neurons or

glia, some indicating changes in cytokine levels in

Alzheimer‟ s disease brain, blood and cerebrospinal fluid (CF).

Elevated levels of IL-1α, IL-1β, IL- 6, TNF-α,

granulocyte-macrophage colony-stimulating factor (GMSF),

IFN-α, type B of IL-8 receptor (IL-8RB) and the receptor for

CSF-1 have been reported in AD brain tissue.[23] There have

also been reports of multiple synergies between cytokines and

constituents of the AD senile plaques, indicating the possible

generation of a vicious circle. Therefore, Aβ plaque protein is

reported to enhance IL-6 and IL-8 secretion by IL-1β-activated

astrocytoma cells, IL-6 and TNF-α secretion by

lipopolysaccharide-(LPS-) stimulated astrocytes and IL-8

secretion by monocytes.[24] The secretion of other proteins

found in senile plaques can also be stimulated by cytokines

Additionally, there might be synergistic effects between

cytokines and Aβ. For instance, IFN-γ is reported to interact

with Aβ, releasing TNF-α and reactive nitrogen species

harmful for neurons. Reports also suggest that IL-1 increases

the degree of Aβ damage in PC12 cells. Pro- inflammatory

cytokines are cytokines promoting inflammation and

anti-inflammatory cytokines are cytokines suppressing the

activity of pro-inflammatory cytokines. Thus, IL-4, IL-10 and

IL-13 are effective B lymphocyte activators, but they are also

effective anti-inflammatory agents. As they are able to inhibit

genes for pro-inflammatory cytokines, such as IL-1, TNF and

chemokines, they are first of all anti-inflammatory cytokines.

Another good example of the pleiotropic characteristic of

cytokines is IFN-γ. It has antiviral activity, like IFN-α and

IFN-β. IFN-γ also activates the pathway disturbing cytotoxic T

cells, but it is thought to be a pro-inflammatory cytokine as it

enhances TNF activity and generates NO. Cytokine biology

and clinical medicine take into consideration the importance of

cytokine functions inducing inflammation, as well as

suppressing inflammation.[24] The ground for this concept lies

in the genetic coding for small mediator molecule synthesis,

upregulated throughout the course of inflammation. The

“balance” between the consequences of pro- inflammatory and

anti-inflammatory cytokines is reported to decide the short term

or long term outcome of the disease. In fact, several studies

suggested that the equilibrium or expression of either

pro-inflammatory or anti-inflammatory cytokines genetically

determine disease susceptibility. Nevertheless, the difficulty in

interpreting some gene linkage studies should be considered.

The production of the inflammatory mediators produced by

microglia and astrocytes around Aβ neuritic plaques is

enhanced in inflammatory states, regulating the intensity and

duration of immune response.[25] There are two agonist

proteins in IL-1 family of cytokines, namely IL-1α and IL-1β,

inducing cell activation after attaching to specific membrane

receptors. Another member is the glycosylated secretory

protein of 23 kDa, IL-1ra, neutralizing the activity of

interleukin -1.[26] Immune responses are successfully initiated

by IL-1, which is of utmost importance in the onset and

evolution of a compound hormonal and cellular inflammatory

cascade. Both humans and rodents have displayed increased

IL-1β levels in the CF and brain parenchyma right after brain

injury.[27] The impact of IL-1 in neuronal degeneration has

also been reported. In astrocytes, it triggers IL-6 production,

triggers iNOS activity and generates M-C SF production.

Moreover, IL-1 increases neuronal acetylcholinesterase activity,

microglial activation and supplementary IL-1 production,




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astrocyte activation and expression of the beta-subunit of S100

protein (S100β) by astrocytes, thus determining a self-

reproducing cycle. The multifunctional cytokine, IL-6, is of

great importance for host protection system], having significant

regulatory effects on the inflammatory response.[28] It is one

of the four-helix bundle cytokines called neuropoietin, with

direct and indirect neurotrophic impact on neurons.[29] Among

IL-6 effects are the promotion of astrogliosis, microglia

activation and the stimulation of acute phase protein

production Castell JV, Andus T, Kunz D, Heinrich PC.[30]

Cytokine cascade initiation and regulation during an

inflammatory response are strongly influenced by TNF-α.

TNF-alpha production as a membrane-bound precursor

molecule of 26 k daltons divided by the TNF-α converting

enzyme, generates an active cytokine with a molecular weight

of 17 k daltons.[31] There are low levels of TNF-α expression

in the normal brain, which burdens the determination of its

exact impact under physiological conditions. In case of

inflammation or illness, TNF-α is predominantly produced by

activated microglia together with more pro-inflammatory

mediators or neurotoxic chemicals. Even if brain-derived

neurotrophic TNF-α is generally combined by glia as a reaction

to pathological stimuli, there have been reports of neuronal

production of TNF-α.[31] Glial cells produce both TNF-α and

IL-1 which in turn initiate further autocrine induction into

cytokine production and astrogliosis. Nevertheless, there are

reports indicating the neuroprotective properties of TNF-α in

Alzheimer’s disease brain.

III. CYTOKINES AND INFLAMMATORY BOWEL DISEASES

Ulcerative colitis (UC) and Crohn’s disease (CD) are immune

related types of inflammatory bowel disease (IBD).[32]

Comprehensive data indicate that IBD is caused by an

inadequate inflammatory response to bacteria in a genetically

exposed host.[33] Additional proof indicates that disease

development is generated by an impaired dialogue between

intestinal flora and components of both inborn and adaptive

immune systems. [33] Cytokines strongly influence immune

functions. The classical T helper Th1/Th2 example triggering

predominant Th1-mediated responses governed by the

production of interferon-γ (IFN-γ) in CD and an excessive

Th2-like inflammation in UC with enhanced production of

IL-13 is joined by extensive information about the function of

inborn immunity in IBD pathogenesis.[34] Therefore, recent

data have demonstrated that: (1) the Th1 and Th2 immune

responses in the mucosa of CD and UC may be in fact

subordinated to an impaired inborn immune response; (2)

regulatory T cell dysfunction might lead to mucosal immune

abnormalities; (3) the newly described Th17 cells also

influence the intestinal inflammatory response in both types of

IBD. T cell differentiation and survival is based on the amount

of key regulatory cytokines produced mainly by macrophages

and dendritic cells.[35] When accompanied by IL- 12 and

IFN-γ, naive CD4+ T cells take up a Th1 phenotype and

activate macrophages that release IL-1, IL-6 and TNF-α. This

generates a positive feedback circle.[36] When accompanied by

IL-4, naive CD4-T cells take up a Th2 phenotypeTh17 is

generated by IL-6, IL-21, IL-23 and transforming growth

factor- β (TGF- β), resulting in the IL- 17 cytokine family and

IL- 22 secretion. Even if there is not enough evidence regarding

the function of Th17 cells, the importance of this type of T cell

population which expresses IL-23 receptors is not contested. It

has been recently proved as an IBD susceptibility gene in

genome-wide association studies (GWAS). On the other hand,

TGF-β and IL-10 adjust naïve T cell differentiation into T

regulatory cell subgroups generating high amounts of IL-10

and TGF-β, being able to inhibit bystander T cell activation.[37]

This could be inadequate in IBD.[38] There is a strong

relationship between these different cell populations in case of

inflammation, such as the negative cross-regulation of Th17

cell differentiation by Th2 cells (IL-4, IL- 27) and Th1 cells

(IFN-γ). The best therapy for IBD in 2010 was represented by

infliximab. But there are some limitations of this chimeric

monoclonal antibody against TNF. Firstly, even if it is widely

used in IBD, 20% of patients still need surgery.[39] Secondly,

approximately 10% of patients don‟ t usually respond to

infliximab and only one-third of IBD patients are in clinical

remission at 1 year. Thirdly, there is an annual risk of loss of

response of 13% per patient-year.[40] Finally, infliximab

treatment can be optimized by combining it with other therapy,

considering the high risk of severe infections and lymphoma.

All these emphasize the immediate need for new drug classes.

One of the most promising future therapies is based on

humanized IL-12/23 antibodies. IL-23 is a basic mediator of

proinflammatory Th17 cell differentiation and expansion. It

increases host susceptibility to IBD in case of IL-23 receptor

polymorphism. IL-23 has displayed effective results in a recent

randomized, controlled trial, especially when infliximab has

been withdrawn. There are ongoing phase III clinical trials in

IBD patients. New cytokine pathways have been identified in

recent studies in the pathophysiology of IBD, representing

potential therapeutic targets. There is ongoing investigation of

multiple cytokines: IL-27, produced mainly by dendritic cells,

acting in Th1 and Th2 cell differentiation; IL-32, produced by

NK cell- activated lymphocytes and epithelial cells, offering a

proinflammatory amplification pathway in the inborn immune

responses to bacteria.[41] IL-31, preferentially produced by T

cells altered towards a Th2 phenotype, influencing acute-phase

inflammation by maintaining proliferation of B and T cells.

There is need for further studies to completely explore their

different functions in human IBD and their biological

significance, in order to ultimately determine their therapeutic

implications.

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