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Interleukin-6 In Systemic Sclerosis
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Interleukin-6: a new therapeutic target in systemic sclerosis?
Steven O'Reilly1, Rachel Cant1, Marzena Ciechomska1 and Jacob M van
Laar1
1Musculoskeletal Research Group, Institute of Cellular Medicine,
Newcastle upon Tyne, UK
Citation: Clinical & Translational Immunology (2013) 2, e4; doi:
10.1038/cti.2013.2
Published online 12 April 2013
Correspondence: Dr S O'Reilly, Musculoskeletal Research Group,
Institute of Cellular Medicine, 4th Floor Cookson Building,
Framlington Place, Newcastle upon Tyne NE2 4HH, UK. E-mail:
rei...@ncl.ac.uk
Received 21 December 2012; Revised 20 February 2013; Accepted 24
February 2013
Abstract
Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical
in mounting an effective immune response.
It is secreted by a wide array of cell types; however, its effector
cells are more restricted, owing to the fact that very few cells,
except lymphocytes and hepatocytes, express the functional membrane
IL-6 receptor thus reducing the number of IL-6-responsive cells.
Trans-signalling, the shedding of the membrane-bound form of the IL-6
receptor into the local microenvironment, greatly increases the range
of cells that can respond.
IL-6 has been demonstrated to have a pivotal role in the pathogenesis
of rheumatoid arthritis, Castleman’s disease and Crohn’s disease
exemplified by the use of an anti-IL-6 biological therapy.
However, IL-6 is also associated with the autoimmune disease systemic
sclerosis (SSc) and has been shown to be directly fibrotic.
Elevated levels of IL-6 are found in SSc patients and this correlates
with skin thickness, suggesting a causal effect.
This review focuses on the role of IL-6 in SSc, a chronic autoimmune
disease with fibrosis.
In particular, we will examine the evidence base of the role of IL-6
in fibrosis in this condition, especially the downstream effector
pathways.
We will then argue why molecular targeting of IL-6 is a promising
therapeutic target in this fibrosing disease.
Keywords: interleukin-6; interleukin-6 signalling; systemic sclerosis;
fibrosis; Th17
http://www.nature.com/cti/journal/v2/n4/full/cti20132a.html
---------------------------------
Dietary alpha-linolenic acid increases TNF-alpha, and decreases IL-6,
IL-10 in response to LPS: effects of sesamin on the delta-5
desaturation of omega6 and omega3 fatty acids in mice.
Prostaglandins Leukot Essent Fatty Acids. 1998 Mar;58(3):185-91.
Chavali SR, Zhong WW, Forse RA.
Department of Surgery, Harvard Institute of Medicine, Beth Israel
Deaconess Medical Center and Harvard Medical School,
Boston, MA 02215, USA.
Sesamin (a non-fat portion of sesame seed oil) inhibits delta-5
desaturase activity resulting in an accumulation of dihomo-gamma-
linolenic acid (DGLA) which can displace arachidonic acid (AA) and
decrease the formation of pro-inflammatory mediators.
We investigated the effects of consumption of diets containing 0.25wt
%
sesamin and 15 wt% safflower oil (SO) (providing 12% of the added fat
as linoleic acid) or a 15 wt% 2:1 mixture of linseed oil and SO
(LOSO)
(providing 6% alpha-linolenic acid and 6% linoleic acid) for 3 weeks
on the liver membrane fatty acid composition and on the production of
prostaglandin (PG) E2, TNF-alpha, IL-6 and IL10 in mice.
Consumption of sesamin-supplemented SO and LOSO diets resulted in a
significant increase in the levels of 20:3omega6 (DGLA), suggesting
that sesamin inhibited delta-5 desaturation of omega6 fatty acids.
In animals fed LOSO diets, the levels of alpha-linolenic acid,
eicosapentaenoic acid (EPA) and of docosahexaenoic acid (DHA) were
elevated with a concomitant decrease of arachidonic acid (AA) in the
liver membrane phospholipids.
Further, in animals fed LOSO diets with or without sesamin, an
increase
in the circulating levels of TNF-alpha was associated with a
concomitant
decrease in PGE2.
Despite a lack of differences in the levels of AA, the PGE2 levels
were
significantly lower in mice fed sesamin-supplemented SO compared to
those fed SO alone.
Thus, these data suggest that irrespective of the availability of a
specific
fatty acid as a substrate, through regulating the PGE2 synthesis,
the production of TNF-alpha could be modulated.
PMID: 9610840
---------------------------------
"IL6-induced BBB defect precipitates iron accumulation"
Abnormal iron deposition associated with lipid peroxidation in
transgenic mice expressing interleukin-6 in the brain.
J Neuropathol Exp Neurol. 1998 Mar;57(3):268-82.
Castelnau PA, Garrett RS, Palinski W, Witztum JL, Campbell IL, Powell
HC.
Department of Pathology (Neuropathology), School of Medicine,
University of California San Diego and the Veterans Affairs Research
Service, La Jolla 92093-0612, USA.
Transgenic mice, named GFAP-IL6, that express interleukin-6 in
astrocytes in the central nervous system (CNS) have a constitutive
blood-brain barrier (BBB) defect and develop a progressive
neurodegenerative disease.
Based on ultrastructural observations showing electron-dense pigment
in the brain of the GFAP-IL6 mice, we hypothesized that iron
metabolism
was altered in the brains of these animals.
Enhanced histochemical methods revealed abnormal iron deposition in
the cerebellum from 1 month of age that worsened with progression of
the
disease.
Immunohistochemical analysis of iron-binding proteins (IBP) showed
increased ferritin immunoreactivity and a decreased signal from the
transferrin receptor in symptomatic animals.
Atomic absorption spectroscopy revealed a 40% increase of total iron
concentration in the cerebellum at the symptomatic stage.
In order to obtain evidence that accumulation of this oxidizing metal
was toxic, we looked for the presence of oxidative damage.
Using the MAL-2 antibody, extensive lipid peroxidation (LP) was
detected
in the neocortex and the cerebellum in symptomatic animals.
Ultrastructural analysis indicated lipofuscin deposition at the sites
of
neuro-axonal degeneration and abnormal iron deposition.
These results suggest that the IL6-induced BBB defect precipitates
iron
accumulation in the GFAP-IL6 mouse brain and that subsequent IBP
regulation mediates protective responses.
As these defenses become overwhelmed, the iron overload seems to
promote LP, which may contribute to the neurodegeneration that
ensues.
This transgenic mouse model of IL6-mediated neurodegeneration provides
a
unique opportunity to examine several aspects of iron metabolism in
the brain,
including its entry at the site of the BBB, its distribution through
the IBP, and
its mechanisms of toxicity.
PMID: 9600219
---------------------------------
Molecule May Drive Multiple Sclerosis-Linked Disorder
Discovery could lead to treatments for transverse myelitis and MS
WEDNESDAY, Oct. 12 (HealthDay News) -- Researchers report that a
single molecule called IL-6 is the cause of transverse myelitis (TM),
an
autoimmune disease in the central nervous system that's related to
multiple sclerosis.
The study found that levels of IL-6 are dramatically elevated in the
spinal fluid of people with TM.
The finding may help in the development of treatments for both TM and
multiple sclerosis.
"This is the first time a single culprit has been identified as
causing a CNS (central nervous system) autoimmune disease," researcher
Dr.
Adam Kaplin, a psychiatrist and assistant professor of medicine at
Johns
Hopkins University School of Medicine, said in a prepared statement.
IL-6 is a chemical messenger that immune system cells use to
communicate with each other. Most TM patients suffer a single attack,
but 15 percent to 30 percent of TM patients go on to develop full-
blown multiple sclerosis. TM usually results in permanent impairment,
including leg and arm weakness, bowel and bladder dysfunction, pain
and paralysis.
The researchers decided to investigate IL-6 because TM patients
suffer from memory impairment and depression.
Previous research implicated IL-6 in mood and concentration
disorders.
The study appears in the October issue of the Journal of Clinical
Investigation.
The U.S. National Institute of Neurological Disorders and Stroke has
more about transverse myelitis.
-- Robert Preidt
SOURCE: Johns Hopkins Medicine, news release, news release, Sept. 22,
2005
Last Updated: Oct. 12, 2005
Copyright © 2005 ScoutNews LLC. All rights reserved
---------------------------------
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
Steven O'Reilly1, Rachel Cant1, Marzena Ciechomska1 and Jacob M van
Laar1
1Musculoskeletal Research Group, Institute of Cellular Medicine,
Newcastle upon Tyne, UK
Citation: Clinical & Translational Immunology (2013) 2, e4; doi:
10.1038/cti.2013.2
Published online 12 April 2013
Correspondence: Dr S O'Reilly, Musculoskeletal Research Group,
Institute of Cellular Medicine, 4th Floor Cookson Building,
Framlington Place, Newcastle upon Tyne NE2 4HH, UK. E-mail:
rei...@ncl.ac.uk
Received 21 December 2012; Revised 20 February 2013; Accepted 24
February 2013
Abstract
Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical
in mounting an effective immune response.
It is secreted by a wide array of cell types; however, its effector
cells are more restricted, owing to the fact that very few cells,
except lymphocytes and hepatocytes, express the functional membrane
IL-6 receptor thus reducing the number of IL-6-responsive cells.
Trans-signalling, the shedding of the membrane-bound form of the IL-6
receptor into the local microenvironment, greatly increases the range
of cells that can respond.
IL-6 has been demonstrated to have a pivotal role in the pathogenesis
of rheumatoid arthritis, Castleman’s disease and Crohn’s disease
exemplified by the use of an anti-IL-6 biological therapy.
However, IL-6 is also associated with the autoimmune disease systemic
sclerosis (SSc) and has been shown to be directly fibrotic.
Elevated levels of IL-6 are found in SSc patients and this correlates
with skin thickness, suggesting a causal effect.
This review focuses on the role of IL-6 in SSc, a chronic autoimmune
disease with fibrosis.
In particular, we will examine the evidence base of the role of IL-6
in fibrosis in this condition, especially the downstream effector
pathways.
We will then argue why molecular targeting of IL-6 is a promising
therapeutic target in this fibrosing disease.
Keywords: interleukin-6; interleukin-6 signalling; systemic sclerosis;
fibrosis; Th17
http://www.nature.com/cti/journal/v2/n4/full/cti20132a.html
---------------------------------
Dietary alpha-linolenic acid increases TNF-alpha, and decreases IL-6,
IL-10 in response to LPS: effects of sesamin on the delta-5
desaturation of omega6 and omega3 fatty acids in mice.
Prostaglandins Leukot Essent Fatty Acids. 1998 Mar;58(3):185-91.
Chavali SR, Zhong WW, Forse RA.
Department of Surgery, Harvard Institute of Medicine, Beth Israel
Deaconess Medical Center and Harvard Medical School,
Boston, MA 02215, USA.
Sesamin (a non-fat portion of sesame seed oil) inhibits delta-5
desaturase activity resulting in an accumulation of dihomo-gamma-
linolenic acid (DGLA) which can displace arachidonic acid (AA) and
decrease the formation of pro-inflammatory mediators.
We investigated the effects of consumption of diets containing 0.25wt
%
sesamin and 15 wt% safflower oil (SO) (providing 12% of the added fat
as linoleic acid) or a 15 wt% 2:1 mixture of linseed oil and SO
(LOSO)
(providing 6% alpha-linolenic acid and 6% linoleic acid) for 3 weeks
on the liver membrane fatty acid composition and on the production of
prostaglandin (PG) E2, TNF-alpha, IL-6 and IL10 in mice.
Consumption of sesamin-supplemented SO and LOSO diets resulted in a
significant increase in the levels of 20:3omega6 (DGLA), suggesting
that sesamin inhibited delta-5 desaturation of omega6 fatty acids.
In animals fed LOSO diets, the levels of alpha-linolenic acid,
eicosapentaenoic acid (EPA) and of docosahexaenoic acid (DHA) were
elevated with a concomitant decrease of arachidonic acid (AA) in the
liver membrane phospholipids.
Further, in animals fed LOSO diets with or without sesamin, an
increase
in the circulating levels of TNF-alpha was associated with a
concomitant
decrease in PGE2.
Despite a lack of differences in the levels of AA, the PGE2 levels
were
significantly lower in mice fed sesamin-supplemented SO compared to
those fed SO alone.
Thus, these data suggest that irrespective of the availability of a
specific
fatty acid as a substrate, through regulating the PGE2 synthesis,
the production of TNF-alpha could be modulated.
PMID: 9610840
---------------------------------
"IL6-induced BBB defect precipitates iron accumulation"
Abnormal iron deposition associated with lipid peroxidation in
transgenic mice expressing interleukin-6 in the brain.
J Neuropathol Exp Neurol. 1998 Mar;57(3):268-82.
Castelnau PA, Garrett RS, Palinski W, Witztum JL, Campbell IL, Powell
HC.
Department of Pathology (Neuropathology), School of Medicine,
University of California San Diego and the Veterans Affairs Research
Service, La Jolla 92093-0612, USA.
Transgenic mice, named GFAP-IL6, that express interleukin-6 in
astrocytes in the central nervous system (CNS) have a constitutive
blood-brain barrier (BBB) defect and develop a progressive
neurodegenerative disease.
Based on ultrastructural observations showing electron-dense pigment
in the brain of the GFAP-IL6 mice, we hypothesized that iron
metabolism
was altered in the brains of these animals.
Enhanced histochemical methods revealed abnormal iron deposition in
the cerebellum from 1 month of age that worsened with progression of
the
disease.
Immunohistochemical analysis of iron-binding proteins (IBP) showed
increased ferritin immunoreactivity and a decreased signal from the
transferrin receptor in symptomatic animals.
Atomic absorption spectroscopy revealed a 40% increase of total iron
concentration in the cerebellum at the symptomatic stage.
In order to obtain evidence that accumulation of this oxidizing metal
was toxic, we looked for the presence of oxidative damage.
Using the MAL-2 antibody, extensive lipid peroxidation (LP) was
detected
in the neocortex and the cerebellum in symptomatic animals.
Ultrastructural analysis indicated lipofuscin deposition at the sites
of
neuro-axonal degeneration and abnormal iron deposition.
These results suggest that the IL6-induced BBB defect precipitates
iron
accumulation in the GFAP-IL6 mouse brain and that subsequent IBP
regulation mediates protective responses.
As these defenses become overwhelmed, the iron overload seems to
promote LP, which may contribute to the neurodegeneration that
ensues.
This transgenic mouse model of IL6-mediated neurodegeneration provides
a
unique opportunity to examine several aspects of iron metabolism in
the brain,
including its entry at the site of the BBB, its distribution through
the IBP, and
its mechanisms of toxicity.
PMID: 9600219
---------------------------------
Molecule May Drive Multiple Sclerosis-Linked Disorder
Discovery could lead to treatments for transverse myelitis and MS
WEDNESDAY, Oct. 12 (HealthDay News) -- Researchers report that a
single molecule called IL-6 is the cause of transverse myelitis (TM),
an
autoimmune disease in the central nervous system that's related to
multiple sclerosis.
The study found that levels of IL-6 are dramatically elevated in the
spinal fluid of people with TM.
The finding may help in the development of treatments for both TM and
multiple sclerosis.
"This is the first time a single culprit has been identified as
causing a CNS (central nervous system) autoimmune disease," researcher
Dr.
Adam Kaplin, a psychiatrist and assistant professor of medicine at
Johns
Hopkins University School of Medicine, said in a prepared statement.
IL-6 is a chemical messenger that immune system cells use to
communicate with each other. Most TM patients suffer a single attack,
but 15 percent to 30 percent of TM patients go on to develop full-
blown multiple sclerosis. TM usually results in permanent impairment,
including leg and arm weakness, bowel and bladder dysfunction, pain
and paralysis.
The researchers decided to investigate IL-6 because TM patients
suffer from memory impairment and depression.
Previous research implicated IL-6 in mood and concentration
disorders.
The study appears in the October issue of the Journal of Clinical
Investigation.
The U.S. National Institute of Neurological Disorders and Stroke has
more about transverse myelitis.
-- Robert Preidt
SOURCE: Johns Hopkins Medicine, news release, news release, Sept. 22,
2005
Last Updated: Oct. 12, 2005
Copyright © 2005 ScoutNews LLC. All rights reserved
---------------------------------
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
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