6. taurine, taurine derivatives and the immune...

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Taurine in Health and Disease, 2012: 101-129 ISBN: 978-81-7895-520-9

Editors: A. El Idrissi and W. L’Amoreaux

6. Taurine, taurine derivatives and the

immune system

Janusz Marcinkiewicz1

and Ewa Kontny2

1Department of Immunology, Jagiellonian University Medical College, Kraków, Poland;

2Department

of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland

1.1. Introduction

Taurine, a non-protein sulfur amino acid, is the most abundant free

amino-acid in the body and plays an important role in several essential

biological processes such as bile acid conjugation, maintenance of calcium

homeostasis, osmoregulation, and membrane stabilization [1,2,3]. Taurine

reaches particularly high concentrations in tissues with high oxidative activity

and in tissues exposed to elevated levels of oxidants (retina, kidney, heart,

immune inflammatory cells) [4,5]. It suggests that cytoprotective properties

of taurine, demonstrated in various in vitro and in vivo studies, attribute

primarily to its antioxidant activity and are not tissue specific [6, 7]. At a site

of inflammation, taurine is known to react and detoxify hypochlorous acid

(HOCl) generated by neutrophil myeloperoxidase–halide system. This

reaction results in formation of less toxic taurine chloramine (TauCl) [8,9].

TauCl, as well as taurine bromamine (TauBr), the product of taurine reaction

with hypobromous acid (HOBr), exerts anti-inflammatory, anti-oxidant, pro-

apoptotic, and antibacterial properties [10,11,12,13]. This review summarizes

Correspondence/Reprint request: Dr. Janusz Marcinkiewicz, Department of Immunology, Jagiellonian

University Medical College, 18 Czysta St., 31-121 Kraków, Poland. E-mail: [email protected]

Janusz Marcinkiewicz & Ewa Kontny 102

Basic functions of taurine are not tissue- specific

Taurine

• Antioxidant

• Osmoregulation

• Membrane stability

• Maintenance of Ca++ concentration

Brain & Retina

Liver

Cytoprotection Homeostasis

Heart & Muscles Immune system

Kidneys

Figure 1. Biological functions of taurine.

our current knowledge concerning the role of taurine and taurine haloamines

(TauCl, TauBr) in innate and adaptive immune system, and their therapeutic

applications.

1.2. Taurine metabolism and tissue distribution

Taurine (2-aminoethanesulfonic acid), a semi-essential sulfur-containing

-amino acid, is present at high concentrations in most tissues, in almost

every animal from the most primitive up to human [1,2]. Taurine is formed

from methionine and cysteine metabolism via hypotaurine in the liver (in

details see Chapter 1). Other cells contain very high concentrations of taurine

due to taurine uptake from the blood, a source of both endogenous and diet

taurine pool [14]. However, the capacity to synthesize taurine varies greatly

among species. Some animals (e.g. carnivals: cats, polar bears) are totally

dependent on taurine-rich diet, while others species (e.g. rats) can live on

totally taurine-free diet [15,16]. The biosynthetic capacity of humans to

produce taurine is limited in neonates (the effect amplified by prematurity)

and also declines with aging and some pathological stages (trauma, sepsis). It

implicates the diet as an important taurine source in these populations [17].

Taurine is not utilized for protein biosynthesis but is found to decay into

isothionate (2-hydroxyethanosulphonate). The most likely intermediate in the

Taurine and immune system 103

conversion of taurine into isothionate would be sulphoacetaldehyde. The

latter compound is formed at a site of inflammation as a result of taurine

interaction with hypochlorous acid, generation of TauCl (N-chlorotaurine)

and final decomposition of TauCl into aldehyde [18,19].

Taurine + HOCl TauCl sulphoacetoaldehyde isothionate

1.2.1. Taurine content of immune cells

In human body taurine is present as a free amino acid and a conjugate

with bile acids. In contrast to low concentrations of taurine in the plasma and

extracellular fluids (ranging from 10-100 M), intracellular concentrations of

taurine can reach up to 80 mM, depending on the cell type [1]. For example,

taurine levels in retina (50-70 mM) and brain (30-40 mM) are much higher

than in lung (10-17 mM) and in liver tissues (~10 mM). High concentrations

of taurine are present in platelets and all blood leukocytes (10-30 mM).

However, particularly high concentrations of taurine are present in

inflammatory immune cells, especially in neutrophils (20-50 mM) [4]. On the

contrary, erythrocytes are the only blood cells with low levels of taurine.

Such great diversity of intracellular concentration of taurine in different

tissues is regulated and maintained by many factors including taurine

transporter (TAUT) [see Chapter 5].

1.3. Taurine and biological functions of the immune cells

High taurine levels in phagocytes and accumulation of taurine in

inflammatory lesions indicates its role in biology of the cells of innate

immunity [20]. All these cells are involved in killing of pathogens at a site of

inflammation. Activated phagocytes generate a variety of microbicidal and

toxic oxidants produced by peroxidase system in these cells. On the other

hand, taurine, a major scavenger for chlorinated (HOCl) and brominated

(HOBr) species will protect the tissue from oxidative stress. Therefore,

taurine will be involved in cytoprotection and regulation of inflammation. As

taurine is present at high concentrations in leukocytes, one may suggest that

taurine deficiency will affect the immune cell functions. Findings from the taurine transporter knockout mice (taut-/- mice) show

strongly decreased taurine levels in a variety of tissues [21]. There is no

evidence concerning the defect of the immune system of these mice while

various pathologies of retina, CSN, cardiovascular and reproductive system

have been observed [22]. Of special importance is the observation that some

of these diseases were characterized by enhanced apoptosis resulting from a


lack of anti-apoptotic taurine-dependent tissue protection [23]. In contrast to

TAUT knockout mice, prolonged taurine deficiency in cats leads to profound

abnormalities in the immune system. It has been shown that a lack of taurine

in the diet of cats results in significant leukopenia and decreased respiratory

burst in neutrophils. Moreover, histological examination of lymph nodes and

spleen revealed depletion of cells from B-cell areas [16].

However, in human, the precise role(s) for taurine in lymphocytes

dependent immune reactions remains unclear. By contrast, it is commonly

accepted that taurine plays an important role in the immune system as an

antioxidant to protect cells, including leukocytes, from the oxidative stress

[7,24].

1.4. Taurine and oxidative stress; The relationship with

innate and adaptive immunity

Oxidative stress is a major factor responsible for tissue damage in

conditions such as infection, acute and chronic inflammation, cancer and

aging. At a site of inflammation oxidative stress is mediated by reactive

oxygen species (ROS) generated to a greater extend primarily by activated

leukocytes (neutrophils, macrophages, eosinophils). ROS play a beneficial

role in host defense against pathogens but they also are responsible for tissue

injury [25,26]. A variety of antioxidants are involved to prevent oxidant-

induced cell damage and to reduce oxidative modification of self

macromolecules, primarily lipids, proteins, and DNA. Antioxidants (“the

antioxidant network”) act through one of three mechanisms: i. they can

reduce the generation of ROS; ii. scavenge ROS; iii. interfere with the action

of ROS.

Taurine can be found at particularly high concentrations in tissues

exposed to elevated levels of oxidants suggesting its role in the alleviation of

oxidative stress [5,27,28]. Indeed, there have been numerous reports

indicating taurine as an effective antioxidant, but the mechanism underlying

its oxidant activity remains unclear. The best established antioxidant action of

taurine is neutralization of hypochlorous acid (HOCl), extremely toxic

oxidant generated by MPO-halide system [9]. This action explains anti-

inflammatory properties of taurine as its reaction with HOCl results in

generation of TauCl, more stable and less toxic anti-inflammatory mediator.

Therefore, taurine may be considered the component of innate immunity with

a special impact on the development of acute inflammation. However, not all

of the antioxidant actions of taurine are related to HOCl because they are

detected in systems lacking neutrophils. Although taurine is incapable of


directly scavenging the classic ROS, it has been suggested that it is an

effective inhibitor of ROS generation. Only recently a novel antioxidant

hypothesis has been described by Schaffer et al. [7], which takes into

consideration the presence of taurine-conjugated tRNAs in mitochondria [in

details see Chapter 5].

Hypotaurine is an intermediate in the biosynthesis of taurine with strong

anti-oxidative properties. Hypotaurine is even a more effective scavenger of

HOCl and HOBr than taurine, however its intracellular concentrations are

much lower than that of taurine (<1 mM) which markedly limits antioxidant

potential of hypotaurine in vivo [5].

1.4.1. Antioxidant taurine activity and links to adaptive immunity

Hypochlorous acid (HOCl), a product of activated neutrophils,

significantly contributes to protein oxidation which occurs at a site of

inflammation. Proteins modified by chlorination change their biological

activity [29-32]. It has been shown in a number of in vitro and in vivo

systems that chlorination of non-self proteins significantly enhances their

immunogenecity [33-36]. Therefore, chlorination of microbial antigens by

neutrophils may play a beneficial role by enhancing immunity to pathogens

and HOCl can act as a natural adjuvant of adaptive immunity [37,38]. On the

other hand, it has been shown that rats immunized with chlorinated self-

collagen II develop IgG specific to rat CII and arthritis [39]. It raises the

question whether in vivo „chlorination” of self-proteins can induce

autoimmunity and whether there is a role for taurine in autoimmunity. In our

opinion, exogenous antigens are modified by HOCl in phagolysosomes of

neutrophils while self antigens may be chlorinated as the result of massive

leakage of HOCl from lysosomes, at a site of inflammation. Therefore, such

conditions may lead to the induction of autoimmune reactions. However, a

risk of induction of autoimmunity by HOCl-modified self antigens is limited

by trapping of free HOCl by taurine to form TauCl. We have shown recently

that taurine, used at physiological concentrations, completely reduced the

ability of HOCl to oxidize mouse albumin and blocked the production of

autoantibodies (Ig anti-mouse albumin) in the immunized mice (manuscript

in preparation).

In conclusion, the data presented above suggest that the major role of

taurine in the immune system is associated with taurine antioxidant

properties, namely, with its ability to react with HOCl and generation of

biologically active taurine chloramine.


1.5. Taurine haloamines (TauCl,TauBr), the physiological

products of peroxidase halide system – metabolism and

chemical properties

TauCl (TauCl; N-chlorotaurine) is the N-chloro-derivative of taurine and

is the primary chloramine produced at a site of inflammation.

Taurine + HOCl TauCl

The first explicit quotation of TauCl was made in 1971 by researchers

from Poland, who found the chlorination of amino acids by the

myeloperoxidase system [8]. In the following years, its chemical properties

were investigated. Nevertheless, only after 20 years it has been demonstrated

that endogenous TauCl plays a role in innate immunity as a component of

acute inflammatory response [40,41]. The assumed biological function of

TauCl is, firstly, the amelioration and termination of the inflammatory process

due to its anti-inflammatory and anti-oxidant properties, and, secondly, the

inactivation of pathogens. In contrast to TauCl, TauBr, the second major

taurine derivatives, has attracted little attention because the extracellular

concentration of bromide is at least 1,000-fold lower than that of chloride.

However, brominating species (HOBr, TauBr) are more potent antimicrobial

agents than their chlorinating partners (HOCl, TauCl) [42-44]. In this review

we discuss data showing chemical and biological properties of both major

haloamines generated at a site of inflammation, namely TauCl and TauBr.

1.5.1. In vivo generation of TauCl and taurine bromamine

(TauBr)

Oxidants generated by activated phagocytes (neutrophils, monocytes,

eosinophils) play a central role in host antimicrobial defenses but may also

damage host tissue. Upon contact with a pathogen, activated phagocytes

produce a respiratory burst characterized by intense uptake of oxygen.

Oxidant production begins when a membrane-associated NADPH oxidase

reduces molecular oxygen to superoxide. Then dismutation of superoxide

yields H2O2. In neutrophil phagolysosomes myeloperoxidase (MPO) uses

H2O2 to convert chloride ion to hypochlorous acid (HOCl) [10,45]

Cl- + H2O2 + H

+ → HOCl + H2O

HOCl, extremely toxic oxidant, reacts readily with a variety of biomolecules

including N-H compounds present in the cytosol and extracellular

environment of leukocytes:


R-NH2 + HOCl → R-NHCl + H2O

TauCl (taurine chloramine, N-chlorotaurine): As taurine is the most abundant

free amino-acid in neutrophil cytosol (>60% of the amino acid pool) it

becomes the primary HOCl scavenger to produce TauCl (taurine + HOCl →

TauCl + H2O) [9,10].

NH3+

- CH2 - CH2 - SO3

- + HOCl → NHCl

- CH2 -

CH2 - SO3H + H2O

TauBr (taurine bromamine; N-bromotaurine): At plasma concentrations of

halide (100 mM chloride; 20-100 μM bromide; <1 μM iodide) eosinophil

peroxidase (EPO) preferentially oxidizes bromide (Br-) to produce

hypobromous acid, HOBr [46].

Br- + H2O2 + H

+ → HOBr + H2O

Recent studies have shown that HOBr may also be generated by the

MPO-halide system of neutrophils [44,47].

HOCl + Br- → HOBr + Cl

-

HOCl and hypochlorite ion (OCl-) are therefore mainly produced by MPO,

while HOBr and hypobromite (OBr-) are produced by both EPO and MPO.

HOBr, at physiological pH, reacts readily with amine compounds to form

secondary oxidants such as mono-bromamines, di-bromamines and amino

acid-derived aldehydes. These brominating agents, and HOBr in particular,

contribute to innate immunity by virtue of having the ability to kill micro-

organisms but they may also damage host tissues and contribute to

inflammatory tissue injury [46].

As taurine is the most abundant free amino acid in the leukocyte cytosol,

TauBr is the major bromamine generated in vivo by both eosinophils and

neutrophils.

Taurine + HOBr → TauBr + H2O

1.5.2. In vitro synthesis of TauCl and taurine bromamine (TauBr)

For experimental use taurine haloamines are prepared according to the

following protocols, as described elsewhere [48].

TauCl preparation: TauCl is prepared by dropwise addition of

HOCl/OCl- to equal volume of taurine, both reagents in phosphate buffer (pH

7.4). Taurine is mixed with hypochlorite in excess (1.5 : 1), to avoid the

generation of taurine dichloramine (TauCl2). Each preparation of TauCl is

monitored by UV absorption spectra (λ =200 to 400 nm) to assure the


authenticity of TauCl (λ = 252nm) and the absence of TauCl2 (λ = 300nm)

and free HOCl/OCl- (λ = 292nm). The concentration of synthesized TauCl is

determined using the molar extinction coefficient 429 M-1

cm-1

at A252.

The UV absorption spectra of TauCl and TauBr

210 230 250 270 290 310 330 3500.00

0.25

0.50

0.75

TauCl

nanometers

ab

so

rba

nc

e

A.

230 250 270 290 310 330 350 370 390

0.1

0.2

0.3

0.4

0.5

0.6

TauBr

B.

nanometers

ab

so

rban

ce

The UV absorption spectra of TauCl and TauBr

Figure 2. The UV absorption spectra: A. TauCl (λmax = 252 nm); B. TauBr (λmax =

288 nm). For an experimental approach TauCl and TauBr are commonly used in the

form of aqueous solutions. In addition, subsequently to the successful synthesis of

TauCl in the form of the sodium salt (TauCl-Na), this endogenous compound can be

available in ample quantities for both laboratory and clinical use. Moreover, TauCl-

Na is more stable than TauCl and may be kept in the form of a powder for unlimited

time [49].

Comparison of some biological properties of

two natural oxidants, the products of MPO-halide system:

HOCl TauCl

--------------------------------Oxidative capacity +++ +

Membrane permeability yes no (?)

Cytotoxicity +++ +

Form of cell death induced necrosis apoptosis

Stability in body fluids - +

Primary targets Met> Cys -SH


TauBr preparation: HOBr/OBr- is generated by mixing equimolar

amounts of HOClˉ and NaBr

ˉ. Then, the product of this reaction is mixed with

taurine. The mono-bromamine is obtained with a 10-fold excess of amine over the amount of HOBr/OBr

-. Each preparation of TauBr is monitored by

UV absorption spectra (λ=200 - 400 nm) to assure the authenticity of monobromamine (TauBr). Taurine bromamines (TauBr, TauBr2) have absorption spectra similar to those of chloramines, but shifted 36 nm towards longer wavelengths. The concentration of synthesized TauBr (taurine mono-bromamine) is determined using the molar extinction coefficient 430 M

-1 cm

-1

at A288.

1.5.3. Chemical properties of TauCl and TauBr

Chloramines, derivatives of α-amino acids are relatively unstable and

decompose within minutes to aldehydes. In contrast, N-chloramine derivatives

of -amino acids, such as taurine, are more stable. TauCl stability is

exceptional. In vitro, in aqueous solution, TauCl is decomposed to

sulphoacetaldehyde within days. In vivo, in a presence of many enzymes

TauCl will be degraded faster, but still much slower than other tested

N-chloramines [18, 49, 50].

TauCl, similarly to other N-chloramines, is a mild oxidant with a

capacity to react with a variety of biological targets. The following ranking of

active chlorine compounds, concerning their oxidizing capacity, has been

established: hypochlorite (HOCl/OCl-) > trichloroisocyanuric acid >

chloramine T > taurine dichloramine (TauCl2) > taurine monochloramine

(TauCl) [51]. Both, TauCl and HOCl, react readily with thiols, although

chloramines (TauCl) differ from HOCl in discriminating between low

molecular weight thiols. It has been suggested that TauCl should

preferentially attack proteins with low pKa thiols and this could be important

in the regulatory processes. On the other hand, chloramines (TauCl) react

more slowly with methionine than thiols and therefore oxidize other

molecules than HOCl [52]. For example, HOCl reacts equally well with

cysteine and methionine while TauCl reacts with cysteine 5 times faster than

with methionine. It may explain why N-chloramines (TauCl) react more

extensively with cysteine residues in plasma and isolated proteins than HOCl.

In conclusion, TauCl inactivates enzymes by targeting critical thiols (-SH),

while HOCl inactivates enzymes by targeting critical methionines showing

oxidant specific biological activity [32]. Therefore, HOCl and TauCl will

affect different proteins (enzymes) involved in host defense at a site of

inflammation. Much less is known about reactivity of TauBr with biological

targets. Nevertheless, it is well documented that brominating equivalents of


HOCl and TauCl are less stable molecules but more reactive oxidants

[43, 46]. It has been demonstrated that leukocyte derived ROS differentially

react with hypohalous acids and their derivatives (TauCl, TauBr). For

example, HOCl, HOBr and TauBr are reduced by H2O2 while TauCl is

resistant [12,48,53]. Therefore, TauBr activity in vivo depends on the

presence of H2O2 and catalase, an enzyme degrading hydrogen peroxide. By

contrast, TauCl activity seems to be not affected in the presence of other

respiratory burst products of activated neutrophils at a site of inflammation.

1.6. The role of taurine haloamines in the immune system: In

innate (acute inflammation) and adaptive immunity

1.6.1. TauCl and TauBr antimicrobial capacity

It has been well known that oxidants generated by phagocytes at a site of

inflammation are involved in host defense against microbes. Among them,

hypohalous acids (HOCl, HOBr), extremely strong microbicidal agents, play

a crucial role in killing of pathogens by neutrophils and eosinophils

[25,45,46,54]. Taurine haloamines (TauCl, TauBr), less toxic and long-lived

oxidants, also contribute to the killing of microbes in vivo. Bactericidal,

fungicidal, antiviral and antiparasitic activity of both halaoamines has been

demonstrated in a number of papers [50, 53, 55-59].

TauCl, the product of activated neutrophils, reaches very low

concentrations (<100 M) at a site of inflammation. At these physiological

concentrations and at neutral pH, TauCl shows very weak antimicrobial

activity. However, in acidic milieu (pH 4-6), typical in inflammatory

environment, the ability of TauCl to kill pathogens increases significantly

[49,60]. This effect can be explained by the formation of TauCl2 (taurine

dichloroamine), the taurine derivative markedly more toxic than TauCl [50].

Moreover, drastic enhancement of TauCl microbicidal activity was observed

in the presence of ammonium chloride (NH4+). The reason for this increased

activity can clearly be attributed to the formation of monochloramine

(NH2Cl), extremely effective natural antiseptic agent [61]. Moreover, the

transfer of the active chlorine from TauCl to amino groups of molecules of

both pathogens and hosts (transhalogenation) also enhances its activity.

TauCl antimicrobial capacity together with its outstanding tolerability allows

to apply TauCl as a local antiseptic, at a high concentration (1% aqueous

solution) [60,62,63].

TauBr, in contrast to TauCl, seems to be effective microbicidal agent

even at very low physiological concentrations. We have shown that at neutral

pH, TauBr, similarly to HOCl, exerts strong microbicidal activity even at


concentrations <10μM [58,64]. In these conditions TauCl did not kill

bacteria. Moreover, Gaut et al. [44] have shown that addition of low

concentration of Br- (1μM) markedly increases bactericidal activity of the

complete MPO - H2O2 – Cl- system in vitro. Therefore, one may suggest that

physiologically plausible variations in Br- concentration will support

neutrophil dependent defence system (HOCl/TauCl) by formation of HOBr

and TauBr, very strong bactericidal agents. Importantly, TauBr, in contrast to

HOCl, even at high microbicidal concentrations (~100μM) does not exert

cytotoxic activity. The contribution of chlorinating and brominating oxidants

to pathogen killing, to the regulation of inflammatory cells function and to

tissue injury also depends on the interactions with other biologically active

agents present at a site of inflammation. For example, activity of HOCl may

be neutralised by both, nitrites and H2O2, while activity of TauBr is affected

only by the presence of H2O2 [12].

1.6.2. Anti-inflammatory properties of TauCl and TauBr; The

regulation of acute inflammation

Acute inflammation is characterized by a massive neutrophil infiltration

and generation of a variety of inflammatory mediators such as cytokines (e.g.

IL-1, IL-6, IL-8, IL-12, TNF-α), eikosanoids (PGE2), nitric oxide (NO), and

ROS including HOCl, the major oxidant of the neutrophil myeloperoxidase

system [10,25]. During the development of inflammation other cells such as

macrophages, mast cells and endothelial cells, also contribute to generation

of pro- and anti-inflammatory mediators. The latter control the intensity of

inflammation and finally are responsible for its termination.

Studies from many laboratories have demonstrated that TauCl, the

product of reaction of HOCl with Tau, exerts both bactericidal and anti-

inflammatory properties [12,40,41,53,65-70]. Recently, we have shown that

also taurine bromamine (TauBr), the product of reaction of HOBr with Tau,

exerts similar biological properties [12]. Nevertheless, many more studies are

referred to TauCl action. TauCl decreases production of pro-inflammatory

mediators by activated macrophages [71,72], neutrophils [66], fibroblast-like

synoviocytes [73], dendritic cells [74], monocytes [75] and glial cells [76].

TauCl was described to inhibit production of proinflammatory cytokines

(TNF- , IL-1 and IL-6) as well as decrease activity of matrix

metalloproteinases which contribute to the tissue damage [77-79]. It has been

also shown that pre-treatment with TauCl inhibited LPS-dependent induction

of nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2) [41,71,80].

Therefore TauCl reduces the production of crucial inflammatory agents, nitric

oxide (NO) and prostaglandin E2 (PGE2). All these activities of TauCl are


associated with inhibition of different inflammatory mediators. Such anti-

inflammatory properties together with the capacity of TauCl to induce

leukocyte apoptosis suggest that TauCl can be involved in the termination of

acute inflammation [81].

Although, the precise mechanism remains uncertain, much interest is

now focused on the inhibition of NF-κB signalling by TauCl [72,80,82-84].

NF-κB is a major transcription factor that regulates expression of a large

number of genes coding for cytokines, adhesion molecules and other

components of the inflammatory response [85]. In non-stimulated cells,

NF-κB is retained in the cytoplasm as a complex with inhibitory proteins

known IκB. Upon stimulation, IκBα is phosphorylated and degraded by the

proteasome. The degradation of IκBα unmasks the nuclear localization of

NF-κB, allowing translocation into the nucleus and subsequent initiation of

gene expression. It has been demonstrated that TauCl depresses NF-κB

migration into nucleus of activated alveolar macrophages cell line (NR8383

cells) and leads to more sustained presence of IκB in the cytoplasm [80].

Finally it has been estimated that inhibition of NF-κB activation by TauCl is

consistent with the oxidation of IκBα at Met45

, rendering it resistant to

degradation [83].

Additional experiments demonstrated that TauCl, a membrane non-

permeable chloramine, does not directly oxidize intracellular methionine.

TauCl acts through chlorine exchange with other amines (e.g. glycine) to

form more permeable chloramine. TauBr, in contrast to TauCl, is highly

membrane-permeable. It has been demonstrated that TauBr inhibits

degradation of IκBa and TNF induced NF-κB activation [86]. These results

clearly indicate that TauBr exerts anti-inflammatory effects by a similar

process to that of TauCl.

Whether TauCl and TauBr, the components of innate immune system,

play a significant role in inflammation, it is an additional question. In contrast

to well documented in vitro biological activities of both taurine derivatives,

their contribution to host defence against pathogens and to the regulation of

inflammatory response is difficult to prove. The immune system is

characterized by exceptional redundancy and apart from taurine haloamines

uses a great battery of antibacterial and anti-inflammatory agents.

1.6.3. Anti-oxidant properties of TauCl and TauBr

It is generally accepted that taurine protects cells against oxidative injury

[7]. Different mechanisms may contribute to taurine-mediated reduction of

ROS in oxidative stress, as described in paragraph 4. However, in acute

inflammation, which is characterized by neutrophil infiltration and generation


of ROS by MPO-halide system, taurine antioxidant activity is primarily

related to the neutralization of HOCl, a strong oxidant with microbicidal and

cytotoxic activity. It is also well known that TauCl and TauBr, the products

of taurine reaction with HOCl and HOBr, respectively, are weak oxidants

with anti-inflammatory properties [7,11,65,66]. Interestingly, these mild

oxidants may also show antioxidant-like biological effects. Firstly, TauCl

suppresses the activity of phagocytic cells, thereby reducing their ability to

consume oxygen and the induction of respiratory burst. In addition, TauCl

reduces production of ROS by increasing the expression of peroxiredoxin-1,

thioredoxin-1 and heme oxygenase-1 (HO-1), the anti-oxidant enzymes

normally induced by activation of NF-E2-related factor-2 (Nrf2) [87].

Especially, the induction of HO-1 plays an important role in tissue

homeostasis as HO-1 is a key molecule of the integrated response to

oxidative stress. HO-1 is the rate–limiting enzyme responsible for heme

catabolism. The products of HO-mediated heme degradation regulate

important biological processes including oxidative stress, inflammation,

apoptosis, cell proliferation and angiogenesis [88]. Degradation of pro-

oxidant free heme by HO-1 leads to the generation of biliverdin (an anti-

oxidant agent), free iron (rapidly exhausted by ferritin) and carbon monoxide

(an anti-inflammatory agent) [89,90]. Moreover, HO-1 controls the

availability of the heme for synthesis of enzymatic heme proteins (e.g. COX-2,

iNOS), and generates CO, which binds to the heme moiety of heme proteins

thus affecting their enzymatic activity. HO-1 expression at a site of

inflammation is induced by various stimuli.

Taurine itself did not affect the expression of HO-1 protein. However, its

derivatives, TauCl and TauBr, in a similar, dose dependent manner,

significantly enhanced in vitro the expression of HO-1 in various non-

stimulated and stimulated cells (macrophages, endothelial cells, dendritic

cells) [87,91-93]. These properties of taurine derivatives seem to be very

important for their action in vivo. One may speculate that at a site of

inflammation TauCl derived from neutrophils or TauBr derived from

eosinophils induces HO-1 in neighbouring non-activated cells to protect them

against oxidative stress.

Interestingly, HO-1 exerts anti-inflammatory properties similar to TauCl.

For example, TauCl and HO-1 inhibit the production of pro-inflammatory

cytokines and inhibit the generation of nitric oxide in LPS-activated

phagocytes [71]. In addition, the same stimuli may activate neutrophils for

generation of TauCl and HO-1 (both agents may co-exist in the same cells),

at a site of inflammation [37,94]. Therefore, it is reasonable to expect that

TauCl and HO-1 will cooperate to suppress the generation of ROS as a part

of common response to oxidative stress.


HO-1

MPO – halide system

++

Taurine haloamines, the products of MPO-halide system, a physiological link between

cysteine pathway and heme-oxygenase system. A redundancy of antioxidants

InflammationOxidative stress

Cysteine

HOCl/HOBr

TauCl/TauBr

GSHTaurineTaurine

AntiAnti--

inflammatoryinflammatory

effectseffects

((--))

Figure 3. Taurine and taurine haloamines – components of “the antioxidant network”.

1.6.4. TauCl as a link between innate and adaptive immunity

Primary immunoregulatory (anti-inflammatory) role of taurine

haloamines (TauCl, TauBr) is associated with innate immunity and the cells

of acute inflammation. However, at a site of inflammation the cells of

adaptive immunity are also exposed to their action. Therefore, one may

speculate that dendritic cells (DCs), the primary antigen presenting cells

(APCs), will be affected by taurine haloamines in vivo. It has been shown

that TauCl differentially inhibits the generation of DC derived inflammatory

cytokines (IL-6, IL-12, TNFα) [74]. Furthermore, TauCl selectively modulats

the ability of DC to induce IL-2 and IL-10 from T cells [95]. It suggests, that

at a site of inflammation (a gateway of antigens entry), TauCl may play a role

in maintaining the balance between the inflammatory response (innate

immunity) and the induction of an antigen-specific immune response. The

fundamental importance of taurine/taurine derivatives in adaptive immunity

need to be revealed using genetic manipulation.

1.7. Taurine derivatives in chronic inflamation: TauCl and

rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic immune-mediated joint disease that

affects approximately 1% of the population and results in disability, impaired


Taurine; Taurine derivatives & Immune System

Taurine

Taurine haloamines

Innate immunity

Protein oxidation

Acute inflammation

Oxidative stress

Host defense

Immunopotentiation

Autoimmunity

Adaptive immune system

Chronic inflammation

Figure 4. Taurine haloamines as a link between innate and adaptive immunity.

quality of life and decreased life expectancy. The disease is characterized by

inflammation of the synovium and progressive destruction of joint cartilage

and bone. Although the etiology of RA is not fully understood, the

participation of both genetic and environmental factors in the process has

been proved. Moreover, repeated activation of innate immunity and

deregulated adaptive immunity are thought to contribute to the chronicity of

inflammatory response, breakdown of self-tolerance and development of

autoimmune events [96]. The introduction of novel biological therapies (e.g.

cytokine antagonists, B cell depletion, T cell co-stimulation blockers)

markedly improved clinical outcomes in RA. However, impressive efficacy is

only seen in about half of patients. Therefore, targeting of other cell types

that are active players of local inflammatory and destructive response (e.g.

synoviocytes) seems to represent a new promising therapeutic approach.

1.7.1. Normal and rheumatoid arthritis synovium

The lining layer of joint cavity, named the synovium, is organized as a

loose association of cells submerged in a bed of extracellular matrix.

Macrophage-like synoviocytes (MøLS), originating from bone marrow

myeloid lineage, clear the joint from microorganisms and cellular debris

while mesenchymal fibroblast-like synoviocytes (FLS) synthesize components

of extracellular matrix and synovial fluid. Homotypic aggregation of FLS


mediated by cadherin-11 creates spatial organization of the intimal lining

layer. Interestingly, cadherin-11 deficient mice lack defined synovial intimal

lining in diarthroidal joints. Moreover, these mice are relatively resistant to

experimental induced arthritis, as evaluated by determination of joint

inflammation and destruction [97]. This observation points out to FLS as the

active and critical participants of pathologic process resulting in arthritic joint

destruction.

In RA the synovium transforms to a hyperplastic, invasive tissue [96,98].

The sublining layer is infiltrated by the immune cells (T and B lymphocytes,

dendritic cells) that form ectopic lymphoid tissue, where autoantibodies are

produced. By contrast, neutrophils pass through the synovium and

accumulate in synovial fluid, reaching up to 5x109 cells. The number of

MøLS and FLS also rises dramatically and the intimal lining expands from

1-2 cells depth to a depth of up 10-20 cells. Both types of synoviocytes

display a highly activated phenotype. The macrophage-like synoviocytes

produce numerous pro-inflammatory cytokines (e.g. IL-1 , TNF),

chemokines and growth factors that in turn induce FLS to synthesize their

own pattern of mediators, especially IL-6, prostanoids and matrix

metalloproteinases (MMPs). By secretion of soluble factors and direct

cell-to-cell interaction via adhesion molecules synoviocytes not only

perpetuate inflammation but also support survival and differentiation of

lymphocytes. At the cartilage-bone interface the expansive synovial tissue,

called pannus, invades the cartilage and erodes into the bone. Bone is

resorbed by osteoclasts, while FLS are the primary effectors of cartilage

destruction because these cells produce huge amount of proteases and have

unique invasive properties. Several mechanisms (e.g. overexpression of

oncogenes, somatic mutations, increased activity of telomerase) have been

proposed to explain an unusual aggressive behavior of rheumatoid FLS. It is

likely that imprinting due to chronic cytokine exposure and longstanding

genotoxic milieu (e.g. oxidative stress) play the major causative role [98].

1.7.2. Impaired generation of TauCl by rheumatoid synovial

neutrophils

Neutrophils recruited into the site of inflammation generate a large

number of highly reactive oxidants, including HOCl - the major microbicidal

agent. However, an excessive generation of HOCl results in oxidative tissue

damage. To prevent this unwanted deleterious event HOCl is trapped by a

dominant free amino acid taurine and converted to TauCl. TauCl is endowed

with potent anti-inflammatory properties and acts as an important

immunoregulatory factor. In rheumatoid joints neutrophils, representing the


major source of TauCl, are recruited by chemokines into synovial fluid, where

they exhibit features indicative of partial activation and functional

"exhaustion". Interestingly, neutrophils isolated from synovial effusion of RA

patients generate in vitro less TauCl than their peripheral blood counterparts

[99]. Therefore, local concentration of this compound in RA joints is probably

to low to control inflammatory response. Moreover, an elevation of taurine

plasma level [100] and hypertaurinuria [101] was reported in RA patients,

suggesting disturbed metabolism of this TauCl precursor.

1.7.3. Normalization of pathogenic functions of rheumatoid FLS

by TauCl

Fibroblast-like synoviocytes perpetuate RA synovitis by secreting

numerous soluble pro-inflammatory factors. Among them, VEGF and IL-8

recruit immune cells and trigger angiogenesis, PGE2 mediates vascular phase of

inflammatory response and osteoclastic bone resorption, while pleiotropic IL-6

supports proliferation of FLS, differentiation of T helper lymphocytes into

pathogenic Th17 subset, participates in the bone loss and in erosive process as

well as contributes to systemic symptoms [96,98]. In vitro studies revealed that

at physiologically relevant concentrations (200-500 M) TauCl inhibits

production of IL-8, IL-6 and VEGF [102,103], acting at the transcriptional

level and diminishing DNA-binding activity of crucial transcription factors, i.e.

NF B and AP-1 [73]. Moreover, inhibitory effect of TauCl on the cytokine

synthesis is partly mediated by up-regulation of heme oxygenase-1 [104].

Similarly, TauCl decreases transcription of COX-2 gene, down-regulates

expression of COX-2 protein and generation of PGE2. Because TauCl has

failed to affect constitutive expression of COX-1 isoenzyme, this compound is

considered a physiological and selective inhibitor of PGE2 synthesis associated

with inflammation [106]. Interestingly, taurine bromamine, another taurine

derivative with potential immunoregulatory activity, has been found less

effective in normalization of these pro-inflammatory RA FLS functions [103].

Matrix metalloproteinases are proteases of different substrate

specificities that altogether participate in irreparable proteolytic degradation

and in the remodeling of the extracellular matrix. In rheumatoid joints these

enzymes are primarily produced by FLS. In IL-1 -stimulated FLS TauCl has

been shown to inhibit the expression of collagenases (MMP-1 and MMP-13),

that play a dominant destructive role in RA, without affecting constitutive

expression of gelatinases (MMP-2 and MMP-9). Interestingly, TauCl exerts

this inhibitory effect by different mechanisms as down-regulation of MMP-1,

but not MMP-13, has been mediated mainly via stabilization of NF B

inhibitor [79].


Synovial hyperplasia in RA is caused by migration of MøLS from

periphery and by a local growth of FLS. The latter event is likely caused by

imbalance between cell proliferation and death, because the synovial

environment promotes survival of FLS and discourages their deletion by

apoptosis [98]. TauCl has been proved to counteract this abnormality in vitro.

Acting in a dose-dependent manner TauCl efficiently inhibits both

spontaneous and growth factors-triggered proliferation of RA FLS as well as

renders these cells more sensitive to death. At the non-cytotoxic (200-400 M)

concentration TauCl: (i) triggers p53 tumor suppressor-dependent growth

arrest of FLS, accompanied by a characteristic modulation of p53

transcriptional targets, i.e. down-regulation of proliferating cell nuclear

antigen (PCNA) and surviving with concomitant up-regulation of p21 mitotic

inhibitor [107] as well as (ii) induces pro-apoptotic state of these cells,

without execution of apoptosis. The latter event is reflected by caspase 9

activity and translocation of pro-apoptotic Bax protein from cytosol to

membrane and nucleus [108]. However, at sufficiently high concentrations

( 500 m) TauCl causes necrosis of FLS, most probably due to an excessive

ATP deprivation [108].

The above data clearly show that in vitro TauCl dampens several

functions of RA FLS relevant to the pathogenic role of these cells (support of

inflammation, destruction process and synovial hyperplasia). As neither

taurine nor sulphoacetaldehyde, the product of TauCl decomposition, exert

similar regulatory effects on RA FLS [73,79,102,105-107,109], it is likely that

Fibroblast-like synoviocytes

Inflammation Synovial

hyperplasia

Angiogenesis

& cell recruitment

Cartilage

degradation

Pro-inflammatory cytokines

(IL-6, IL-8) Inflammatory mediators

(COX-2 PGE2)

Proliferation

Apoptosis

IL-8, VEGF Degrading enzymes

(MMPs)

Taurine chloramine (Tau-Cl) inhibits:

Tau-Cl normalizes pathogenic activities of rheumatoid fibroblast-like synoviocytes

Figure 5. TauCl impact on rheumatoid synoviocytes (FLS).


that the unique activities of TauCl arise from its oxidative properties and

selective modification of molecules implicated in signal transduction

mechanisms. Moreover, it is likely that TauCl may also affect the pathogenic

functions of RA FLS indirectly, by reducing the synthesis of pro-

inflammatory cytokines (e.g. IL-1 and TNF) by hematopoietic mononuclear

cells, at least in early RA [75,77].

Concluding remarks

Recent advances in understanding biology of rheumatoid FLS suggest

that attempts to target this unique cell type could potentially complement

current therapies. Basing on the above data showing the normalization of an

aggressive behavior of RA FLS by TauCl it is tempting to consider

therapeutic trials aimed at the elevation of local TauCl concentration in

rheumatoid joints. As the ability of rheumatoid synovial fluid neutrophils to

generate TauCl is impaired, application of taurine does not seem to be

rational. Fortunately, drugs that exploit anti-inflammatory properties of

TauCl are available, i.e. sodium salt of N-chlorotaurine (NCT) [60] or

5-aminosalicyltaurine (5-ASA-Tau) [110] and are currently introduced into

human medicine. However, none of these drugs has been tested in RA

patients so far.

1.8. Therapeutic potential of taurine haloamines as antiseptic

and anti-inflammatory agents

Outstanding tolerability of TauCl together with its anti-microbial and

anti-inflammatory properties supported by a high number of in vitro studies

makes this agent a good candidate for clinical use [60,111]. However,

relatively fast degradation of TauCl in liver limits its systemic application.

On the other hand, use of TauCl and TauBr as local antimicrobial and anti-

inflammatory agents is well documented [55,57,62,112-114].

The successful synthesis of the crystalline sodium salt of N-chlorotaurine

(NCT) facilitated its development as an antiseptic [49]. NCT (TauCl) can be

stored long-term at low temperatures, and it has killing activity against wide

spectrum of bacteria, fungi, viruses and parasites. NCT proved to be very

well tolerated by human tissue. A 1% aqueous solution of NCT can be

applied to the eye, skin ulcerations, outer ear canal, nasal and paranasal

sinuses, oral cavity and urinary bladder [60]. Moreover, it has been suggested

that TauCl may be of potential benefit as an adjunctive therapy in peridontal

diseases [115]. Therapeutic efficacy has been shown in external otitis,


purulently coated crural ulcerations and keratoconjunctivitis, so far

[62,63,114].

TauBr is relatively unstable, as compared to TauCl, and therefore has

been ignored as potential new drug in therapy of inflammatory and infectious

diseases. Despite these disadvantages, only recently we have demonstrated

beneficial effects of TauBr in topical therapy of acne vulgaris [113].

Anti-oxidant, anti-inflammatory and anti-bacterial properties of TauBr

have been confirmed in vitro [12]. Interestingly, Propionibacterium acnes, a

potential pathogenic agent of acne vulgaris, is extremely sensitive to TauBr.

At the same non-cytotoxic concentrations, TauBr reduces the generation of

reactive oxygen species (especially H2O2) from activated neutrophils, which

seems to be crucial for reduction the number and severity of inflammatory

lesions in patients with mild to moderate acne [64,116,117]. All these data

strongly supported the idea of application of TauBr for acne topical therapy.

In our pilot clinical study we have compared the efficacy of TauBr cream

with Clindamycin gel, one of the most common topical agents in the

treatment of acne. After 6 weeks, both treatments produced comparable

beneficial results. More than 90% of the patients clinically improved with the

similar reduction in a number of acne lesions (~65%) [113]. Therefore, we

have concluded that TauBr may be a desirable alternative treatment for acne

vulgaris, especially in patients who have already developed antibiotic

resistance [111].

Taurine haloamines are considered to be ineffective as systemic anti-

inflammatory and antimicrobial agents. Attempts to use TauCl in a treatment

of experimental arthritis confirm this negative opinion [118]. However, it has

been shown that daily subcutaneous administration of TauCl had reversible

beneficial effect on the severity and incidence of collagen induced arthritis

(CIA) in mice [119].

To improve the effectiveness of TauCl systemic therapy, a novel strategy

has been proposed for the treatment of inflammatory diseases. Administration

of TauCl should be replaced by an application of taurine itself as a prodrug. It

is expected that taurine supplementation will enhance local formation of

TauCl or TauBr as the result of reaction between exogenous taurine and

endogenous HOCl or HOBr generated at a site of inflammation. Such effects

may be achieved only in the inflammation associated with local infiltration of

neutrophils, the major source of HOCl. So far the beneficial effect of such

strategy has been documented in experimental colitis treated with

5-aminosalicyltaurine (taurine conjugated with 5-ASA) [110,120] and in

collagen induced arthritis (CIA) treated with Taurolidine [64]. Taurolidine

(TRD), a synthetic derivatives of taurine is in vivo degraded to three

products. Methylol-containing TRD breakdown products, taurultam and


taurinamide exert anti-bacterial, anti-endotoxin and anti- adherence activities

[121,122]. Taurine, the third breakdown product of TRD, does not share

those activities but in the presence of HOCl creates TauCl. It has been shown

that TRD administration significantly ameliorates CIA in mice [12].

In conclusion, both in vitro and clinical studies clearly indicate that

taurine derivatives may find their place in therapy of various topical

infections as well as in chronic inflammatory diseases. However, further

studies are necessary to improve their therapeutic effectiveness. Firstly, the

stability of TauCl and TauBr should be increased. Recently, C-methylated

derivatives of TauCl have been invented, which are of interest because of

improved stability at room temperature [60].

1.9. Conclusion

Taurine and taurine haloamines are components of the innate immunity:

They are involved in the host defense against pathogens and in the

regulation of inflammation.

Physiological functions of TauCl/TauBr are associated with the MPO-

halide system of neutrophils.

The fundamental role of taurine in the immune system is to protect

tissues and self molecules from oxidative stress.

Taurine, the partner of peroxidase-halide system of leukocytes, reacts

with HOCl/HOBr to produce taurine haloamines (TauCl/TauBr).

Taurine haloamines, less toxic mild oxidants exert antimicrobial and anti-

inflammatory properties.

Immunoregulatory activities of endogenous TauCl and TauBr are masked

in vivo due to the redundancy of the immune system.

Taurine haloamines (TauCl, TauBr) are promising candidates for a local

treatment of infectious/inflammatory diseases.

1.10. Acknowledgements

This paper was supported by Jagiellonian University Medical College

grants: K/ZDS/001008 and K/ZBW/000575.

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