Biol. pharm. bull. 32(4): 651-656 (2009)
Biol. Pharm. Bull. 32
(4) 651—656 (2009)
The Anti-inflammatory Effects of Methylsulfonylmethane on
Lipopolysaccharide-Induced Inflammatory Responses in Murine
Yoon Hee KIM,a
Dae Hwan KIM,a
and Jin-Kyung KIM*,a
a Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University; c Department ofFood Chemistry and Nutrition, Hallym University; Chuncheon 200–702, Republic of Korea: and b AD Biotech Co., Ltd.;857–4 Toegye-dong, Chuncheon 200–170, Republic of Korea.
Received December 16, 2008; accepted January 6, 2009; published online January 15, 2009
Methylsulfonylmethane (MSM), also known as dimethyl sulfone and methyl sulfone, is an organic sulfur-
containing compound that occurs naturally in a variety of fruits, vegetables, grains, and animals, including hu-
mans. In the present study, we demonstrated the anti-inflammatory effects of MSM in lipopolysaccharide (LPS)-
stimulated murine macrophages, RAW264.7 cells. MSM significantly inhibited the release of nitric oxide and
prostaglandin E by alleviating the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-
stimulated RAW264.7 cells. Furthermore, the levels of interleukin-6 and tumor necrosis factor-
a were decreased
by MSM treatment in cell culture supernatants. Further study indicated that the translocation of the p65 subunit
of nuclear factor (NF)-
kB to the nucleus was inhibited by MSM treatment in LPS-stimulated RAW264.7 cells, in
which it helped block degradation of inhibitor of NF-
kB. In addition, in vivo studies demonstrated that topical
administration of MSM at 500—1250
mg/ear resulted in similar inhibitory activities in 12-O-tetradecanoylphor-
bol 13-acetate-induced mouse ear edema. Collectively, theses results indicate that MSM inhibits LPS-induced re-
lease of pro-inflammatory mediators in murine macrophages through downregulation of NF-
methylsulfonylmethane; inflammation; nuclear factor-k B
Inflammation is a beneficial host response to foreign
There is currently a strong interest in developing new
pathogens or tissue injury, and it eventually leads to the
anti-inflammatory agents from natural products. Methylsul-
restoration of normal tissue structure and function. A normal
fonylmethane (MSM) is found in small amounts in many
inflammatory response is self-limiting and involves down-
foods, including unpasteurized milk, grains, meat, eggs, and
regulation of pro-inflammatory protein expression, increased
fish.13—15) It is also found in a popular dietary supplement
expression of anti-inflammatory proteins, and reversal of the
with a molecular weight of 94.16) Health claims associated
vascular changes that facilitated the initial immune cell re-
with MSM include relief of pain, inflammation, arthritis, al-
cruitment process.1—3) Macrophages play a salient role in the
lergies, certain parasitic infections, and asthma.17—19) In the
inflammatory response and serve as an essential interface be-
present study, we investigated the anti-inflammatory effects
tween innate and adaptive immunity. Following activation,
and underlying mechanisms of action of MSM using LPS-in-
macrophages modulate the expression of accessory mole-
duced inflammatory responses.
cules such as CD14 and toll-like receptor (TLR) 4.4,5) Stimu-lation of TLR4 by lipopolysaccharide (LPS) triggers the re-
MATERIALS AND METHODS
cruitment of the cytoplasmic adaptor protein MyD88 andsubsequently culminates in the activation of downstream sig-
Cell line and Reagents
RAW264.7 murine macrophages
naling pathways: the transcription factor nuclear factor-kB
were obtained from the Korean Cell Bank (Seoul, Korea).
(NF-k B) pathway. These pathways induce the expression of
LPS derived from Escherichia coli
various inflammatory mediators, including nitric oxide (NO),
bol 13-acetate (TPA), dexamethasone and acetone were pur-
prostaglandins (PGs), and inflammatory cytokines.6—9)
chased from Sigma-Aldrich (St. Louis, MO, U.S.A.). The
NF-k B, the key molecule in the inflammatory response, Dulbecco's modified Eagle's medium (DMEM), fetal bovine
is a dimeric transcription factor that is formed by the di-
serum (FBS), penicillin, and streptomycin used in this study
merization of proteins in the Rel family.10) NF-k B activity were obtained from Hyclone (Logan, Utah, U.S.A.). MSMis effected through regulation of the expression of genes was supplied by AD Biotech, Co., Ltd. (Chuncheon, Korea).
that encode inflammatory cytokines, adhesion molecules,
Cell Culture, Cell Viability, and Cytotoxicity Assay
chemokines, growth factors, and inducible enzymes such as
RAW264.7 murine macrophages were cultured in DMEM
cyclooxygenase (COX)-2 and inducible nitric oxide synthase
containing 10% FBS, 100 U/ml penicillin, and 100 m g/ml
(iNOS).10,11) NF-k B activity is usually inhibited in the cyto-
streptomycin at 37 °C in 5% CO . The effects of MSM on
plasm through its association with an endogenous inhibitory
cell viability and cytotoxicity were tested using CellTiter 96®
protein of the Ik -B (inhibitor of NF-k B) family. Upon acti-
One Solution Assay of cell proliferation (Promega,
vation, Ik -B undergoes phosphorylation and degradation,
Madison, WI, U.S.A.) and CytoTox 96® Non-Radioactive
processes that facilitate the movement of NF-k B to the cell
Cytotoxicity Assay (Promega), respectively. RAW264.7 cells
nucleus. Once there, it binds to DNA and induces transcrip-
were plated at a density of 1104 cells/well in a 96-well flat-
bottom plate, and MSM was added to each well at a concen-
∗ To whom correspondence should be addressed. e-mail: firstname.lastname@example.org
2009 Pharmaceutical Society of Japan
tration of 0—10 mg/ml in complete DMEM. After 24 h incu-
above and control group was treated with TPA only. Mouse
bation, viability and cytotoxicity were measured according to
ears were excised 6 h after the last application and homo-
the manufacturer's instructions.
geneized in 50 mM Tris–HCl buffer (pH 7.5) with 1 mM
Measurement of Nitrite and PGE
The amount of ni-
EDTA, and their homogenates were incubated on ice for
trite and PGE produced by the mouse macrophages was
20 min in the presence of 0.1% Troton X-100. The ho-
measured in RAW264.7 cell culture supernatant. RAW264.7
mogenates were centrifuged at 10000g
for 15 min and su-
cells were plated at a density of 1105 cells in a 24-well cell
pernatant was collected for cytokine measurement. Parts of
culture plate with 500 m l of culture medium and incubated
ear were fixed 10% buffered formalin solution, embedded in
for 18 h. They were then treated with various concentrations
paraffin by standard methods and stained with hematoxylin-
(0—10 mg/ml) of MSM in the absence or presence of
eosin (H & E).
500 ng/ml of LPS and incubated for another 24 h. The
Values are expressed as means
amount of nitrite was measured using the Griess reagent sys-
S.E.M. of the results for at least three experiments. One-way
tem (Promega). The amount of PGE produced was meas-
analysis of variance (ANOVA) was used for comparison be-
ured using an enzyme-linked immunosorbent assay (ELISA)
tween the control and treatment groups. p
-values 0.05 were
kit (R&D systems, Minneapolis, MI, U.S.A.), according to
considered statistically significant.
the manufacturer's instructions.
The amounts of tumor necrosis factor
(TNF)-a and interleukin (IL)-6 in the cell culture super-natant were measured using an ELISA kit (eBioscience, San
MSM Was Not Toxic to Murine Macrophages
Diego, CA, U.S.A.). RAW264.7 cells were plated in a 24-
RAW264.7 macrophages were chosen for use in an investiga-
well cell culture plate at a density of 1105 cells and incu-
tion of the anti-inflammatory effects of MSM. We first exam-
bated for 18 h. They were then treated with 0—10 mg/ml of
ined whether MSM has cytotoxicity in RAW264.7 cells. No
MSM in the absence or presence of 500 ng/ml of LPS and in-
notable cytotoxicity was observed when the cells were ex-
cubated for another 24 h. The culture supernatant was col-
posed up to 10 mg/ml for 24 h (Fig. 1). Since MSM did not
lected and assayed according to the manufacturer's instruc-
show cytotoxic effects up to 10 mg/ml, we used MSM at a
concentration of 0—10 mg/ml for the subsequent experi-
Western Blot Analysis
Cells were washed with ice-cold
PBS and scraped, and then whole cell lysates and cytoplas-
MSM Inhibits the Release of NO and PGE by Reduc-
mic and nuclear proteins were extracted using PRO-PREP
ing iNOS and COX-2 Expression in LPS-Stimulated
Protein Extraction Solution (iNtRON Biotechnology, FL,
We initially determined the concentration
U.S.A.) and a Nuclear Extract Kit (Active Motif, CA,
of LPS that causes inflammatory reaction, such as production
U.S.A.), respectively. Twenty micrograms of protein was of inflammatory mediators and Ik -Ba degradation. Both NO,resolved in a loading buffer for sodium dodecyl sulfate
IL-6 production and Ik -Ba degradation were induced at con-
(SDS)–PAGE, electrophoresed on SDS/polyacrylamide gels,
centrations of 10—1000 ng/ml LPS (Fig. 2). Based on these
and electroblotted onto polyvinylidene difluoride (PVDF)
data, we used 500 or 1000 ng/ml of LPS in order to induce
membranes. The membranes were then blocked in Tris-
inflammatory responses in the rest of the experiments.
buffered saline (TBS)-Tween 20 solution containing 5% non-
In order to assess the anti-inflammatory activities of
fat dry milk and incubated overnight at 4 °C with specific an-
MSM, RAW264.7 cells were exposed to LPS in the presence
tibodies against iNOS (BD Biosciences, San Jose, CA,
or absence of MSM, and the level of nitrite, a stable metabo-
U.S.A.), COX-2 (BD Biosciences), Ik -Ba (BD Biosciences),
lite of NO, was measured in the medium. As shown in Fig.
NF-k B p65 (Cell Signaling Technologies Inc., Beverly, MA,
3A, MSM inhibited LPS-induced NO production in a dose-
U.S.A.), b -actin (Sigma), and lamin B (Santa Cruz Biotech-
nology, Santa Cruz, CA, U.S.A.). Proteins were visualized
Since PGE is another key inflammatory mediator, we in-
using goat anti-rabbit or mouse antibody conjugated to
vestigated the effects of MSM on PGE production in LPS-
horseradish peroxidase and a chemiluminescence Western
stimulated RAW264.7 cells. Similar to the findings related
blotting detection system (ECL PlusTM Western BlottingReagents, Amersham Biosciences, Boston, MA, U.S.A.).
Mouse Ear Inflammation Induced by Multiple Applica-
tions of TPA
We assessed the anti-inflammatory activity of
MSM by measuring TPA-induced ear edema in mice. Six-week-old female ICR mice were purchased from ORIENTBIO Inc. (Seongnam, Korea) and maintained under specific-pathogen-free conditions at the animal facility of HallymUniversity (Chuncheon, Korea). Inflammation was inducedthrough topical application of TPA (2.5 m g/ear) dissolved inacetone (20 m l) on days 1, 3, 5, 7 and 10 to the inner andouter surfaces of each ear of mice (5 per group) with the aidof a micropipette. The MSM (50, 500, 1250 m g/ear) or dex-
Effects of Methylsulfonylmethane (MSM) on Viability and Cyto-
amethasone (0.05 mg/ear) was administered topically daily
toxicity in Murine Macrophages
for 10 consecutive days. The blank group was given topical
RAW264.7 cells were treated with 0—10 mg/ml of MSM for 24 h. Cell viability and
cytotoxicity were determined as described in Materials and Methods. The results are re-
applications of acetone in the same regimen as described
ported as meansS.E.M. for three independent experiments.
Effects of LPS on Production of Inflammatory Mediators and Degradation of Ik -Ba
RAW264.7 cells were treated with 0—1000 ng/ml of LPS for 24 h. The NO (A) and IL-6 (B) concentrations in cell culture supernatants were measured as described in Materials
and Methods. The results are reported as meansS.E.M. for three independent experiments. Significant differences from cells treated with 0 ng/ml LPS are indicated as follows:
0.001. (C) RAW264.7 cells were treated with 0—1000 ng/ml of LPS for 30 min. The 50 mg of protein obtained from whole cell lysates were resolved on 10% SDS-PAGE.
Western blot analysis was performed as described in Materials and Methods. b -Actin was used as a loading control.
Effects of Methylsulfonylmethane (MSM) on Production and Expression of Inflammatory Mediators
RAW264.7 cells were treated with 0—10 mg/ml of MSM in the presence of LPS (500 ng/ml) for 24 h. The NO (A) and PGE (B) concentrations in cell culture supernatants were
measured as described in Materials and Methods. The results are reported as meansS.E.M. for three independent experiments. Significant differences from cells treated with LPSin the absence of MSM are indicated as follows: ∗ p
0.05, ∗∗ p
0.01, ∗∗∗ p
0.001. The 20 mg of protein obtained from cell lysates was resolved on 8% and 10% SDS-PAGE foriNOS and COX-2, respectively (C). Western blot analysis was performed as described in Materials and Methods. b -Actin was used as a loading control.
Effects of Methylsulfonylmethane (MSM) on the Production of LPS-Induced Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-a Production in
RAW264.7 cells were treated with 0—10 mg/ml of MSM in the presence of LPS (500 ng/ml) for 24 h. The cell culture supernatants were then collected, and the amounts of re-
leased IL-6 (A) and TNF-a (B) were measured as described in Materials and Methods. The results are reported as meansS.E.M. for three independent experiments. Significantdifferences from cells treated with LPS in the absence of MSM are indicated as follows: ∗∗∗ p
to nitrite accumulation, treatment of RAW264.7 cells with
COX-2 was responsible for the inhibition of NO and PGE2
500 ng/ml of LPS led to a significant increase in PGE pro-
duction. Consistent with the nitrite accumulation, PGE pro-
MSM Reduces the Production of Pro-inflammatory
duction was blocked by MSM treatment (Fig. 3B).
Cytokines in LPS-Stimulated RAW264.7 Cells
In order to determine the mechanism by which MSM re-
attempted to examine the potential effects of MSM on the
duces LPS-induced NO and PGE production, we studied the
production of the pro-inflammatory cytokines, IL-6 and
effect of MSM on iNOS and COX-2 protein expression in
TNF-a . RAW264.7 cells were incubated with MSM in the
RAW264.7 cells using Western blot analysis. As shown in
presence of 500 ng/ml of LPS for 24 h, and IL-6 and TNF-a
Fig. 3C, iNOS and COX-2 protein expression were markedly
levels were evaluated in the culture supernatants. Because of
induced in RAW264.7 cells after treatment with 500 ng/ml of
LPS exposure, the IL-6 and TNF-a level had significantly in-
LPS for 24 h. This induction was suppressed by MSM treat-
creased to 888.353.6 and 12224.0178.2 pg/ml, respec-
ment in a dose-dependent manner. These results indicate that
tively. MSM treatment (10 mg/ml) prevented significant in-
MSM-induced reduction in the expression of iNOS and
creases in IL-6 and TNF-a levels, holding them at 21.98.5
and 8528.0487.1 pg/ml, respectively (Fig. 4).
flammation. Ear edema was measured in the ears prior to and
MSM Inhibits Degradation of I
a and Nuclear
at 6 h following treatments. As shown in Figs. 6A and B, ex-
Translocation of NF-
kB p65 in LPS-Stimulated
posure to TPA resulted in marked increases in skin thickness.
Finally, we examined NF-k B activation
Topical application of acetone (vehicle) did not alter the skin
to determine the molecular mechanisms by which MSM in-
thickness significantly. However, MSM (500, 1250 m g/ear) or
hibits LPS-induced inflammatory responses. NF-k B is a
dexametasone significantly inhibited the TPA-induced in-
major transcription factor involved in the release of proteinsthat mediate the inflammatory response, and the degradationand phosphorylation of Ik -B are necessary to release NF-k Bfrom the cytoplasmic NF-k B/Ik -B complex and to allow itssubsequent translocation to the cell nucleus. We evaluatedthe effect of MSM on NF-k B activation to determine if it ismediated by Ik -B degradation. We observed that LPS-in-duced Ik -B degradation was inhibited after 30 min of expo-sure to MSM (Fig. 5A).
In order to directly investigate the effect of MSM on nu-
clear translocation, we determined NF-k B p65 levels amongboth cytosolic and nuclear proteins. The expression levels ofNF-k B p65 protein were decreased in the nuclear fractionsof cells when they were exposed to MSM, indicating thatMSM inhibits the translocation of NF-k B p65 protein fromthe cytosol to the nucleus (Fig. 5B). These findings suggestthat MSM exerts anti-inflammatory actions by blocking NF-kB signal.
In order to address whether MSM inhibits the activation of
NF-k B induced by other stimuli other than LPS, we used re-combinant mouse TNF-a as a stimuli for NF-k B activation.
MSM also inhibited the degradation of Ik -Ba in TNF-astimulated RAW264.7 cells (Fig. 5C). This result suggests
Effects of Methylsulfonylmethane (MSM) on LPS-Induced Degra-
that MSM blocks NF-k B activation caused by LPS or TNF-a
dation of Ik -Ba and Nuclear Translocation of NF-k B-p65 in Murine
RAW264.7 cells were treated with 0—10 mg/ml of MSM in the presence of 1 m g/ml
Effect of MSM on TPA-Induced Cutaneous Inflamma-
of LPS (A, B) or recombinant mouse TNF-a (C) for 30 min. The 50 m g of protein ob-
We assessed the anti-inflammatory activity of MSM in
tained from whole cell lysates, cytosolic and nuclear fractions of each cell were re-
a TPA-induced ear inflammation model. Increased skin thick-
solved on 10% SDS-PAGE. Western blot analysis was performed as described in Mate-rials and Methods. b -Actin and lamin B were used as loading controls of cytosolic pro-
ening is often the first hallmark of skin irritation and local in-
tein and nuclear protein, respectively.
Effects of Methylsulfonylmethane (MSM) on TPA-Induced Ear Inflammation
Mice were treated with MSM (0, 50, 500, 1250 m g/ear) or dexametasone (50 m g/ear) with topical application of acetone (vehicle) or TPA in acetone. Ear thickness was measured
at 6 h after TPA treatment (A). Representative micrographs of H&E-stained mouse ear cross-sections in TPA-induced ear inflammation model. Ears were harvested 6 h post-treat-ment with acetone vehicle, TPA plus MSM or dexametasone (B). Sections shown are representative of observations from five animals in each group (200 magnification). Serumand ear homogenates were taken 6 h after TPA treatment and examined for the production of the IL-6 using ELISA (C). The results are reported as meansS.E.M. for five mice pergroup. Significant differences from mice treated with TPA in the absence of MSM are indicated as follows: ∗∗ p
0.01, ∗∗∗ p
creases in ear thickness, indicating the therapeutic effect of
degradation and the nuclear translocation of p65. The nuclear
translocation and DNA binding of NF-k B is preceded by the
In addition, topical application of TPA caused a dramatic
degradation of Ik -Ba . Our study indicates that MSM inhib-
increase in the production of IL-6 in plasma and ear ho-
ited LPS-induced inflammatory responses via
mogenates by 6 h after challenge. In contrast, treatment with
degradation of Ik -Ba and the subsequent nuclear transloca-
TPA plus MSM (1250 m g/ear) or dexamethasone reduced IL-
tion of NF-k B p65. Previous studies have shown that the
6 levels significantly (Fig. 6C).
phosphorylation of Ik -B is regulated by a and b isoforms ofIk -B kinase complex (IKK).31) Although we did not observe
the effect of MSM on IKK activity, MSM surely inhibitedIk -Ba degradation. It might represent MSM inhibits IKK ac-
It has been reported that MSM has positive effects on a va-
tivity, Ik -Ba degradation and nuclear translocation of NF-
riety conditions, including osteoarthritis,20) allergic rhinitis,17)
kB p65 in LPS-stimulated RAW264.7 cells.
and cancer.21) However, studies addressing the working
MSM is used orally and topically. Although the optimum
mechanisms of MSM are limited. In the present study, we
dosage has not been clearly defined, the suggested oral thera-
aimed to examine the anti-inflammatory effects of MSM peutic doses are 4—6 g/d.19,20) There is limited formal safetyand to elucidate its underlying mechanisms using murine
data, and no long-term assessment has been performed.
macrophage cells and mouse ear inflammation induced by
However, MSM is rapidly excreted from the body,32,33) and
animal toxicity studies of MSM have shown only minor ad-
We found that MSM dramatically inhibits LPS-induced in-
verse effects with doses of 1.5 g/kg and 2.0 g/kg of MSM for
creases in NO and PGE production through suppression of
90 d.34) This represents a human dose of 30—42 g/d, which is
iNOS and COX-2 expression (Fig. 3). We also found that
equivalent to 5—7 times the proposed maximum recom-
MSM strongly inhibits IL-6 and TNF-a production in LPS-
mended human dose of 6 g/d.34) Another study confirmed
stimulated murine macrophages (Fig. 4). The expression of
that MSM has no toxic effects on either pregnant rats or their
inflammatory mediators such as NO, PGE , IL-6, and TNF-a
fetuses.35) Based on these previous results and the present
is regulated by the key transcription factor, NF-k B.22) NK-
data, we believe MSM is relatively safe and effective for the
kB is maintained in a latent form in the cytoplasm, where it
treatment of inflammatory diseases.
is in complex with the inhibitory Ik -B proteins. The interac-tion of NF-k B with Ik -B masks the nuclear localization sig-
This work was supported by the
nal. Phosphorylation of Ik -B by Ik -B kinase leads to ubiqui-
Regional Innovation Center (RIC) program of the Ministry of
tination of the protein and its subsequent degradation. NF-
Commerce, Industry, and Energy, Republic of Korea and
kB is then free to translocate to the nucleus, where it binds to
Korea Association of Small Business Innovation Research
DNA and induces activation of a wide variety of target genes
(lab-07-1-2), Republic of Korea.
related to the inflammatory response, including iNOS, COX-2, and various cytokines.12,23—26) We showed that MSM
blocks LPS-induced degradation of Ik -Ba and nucleartranslocation of NF-k B p65 in murine macrophages (Fig. 5).
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