Utilization of Dimethyl Fumarate and Related Molecules for Treatment of Multiple Sclerosis, Cancer, and Other Diseases

Abstract

Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF), a related compound, has not been examined in greater details although it has the potential as a therapeutic drug for MS and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species. However, other mechanisms have also been described, which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage, osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article, we will touch on some of these diseases with an emphasis on the effects of DMF and MMF on various immune cells.

Full text

July 2016 | Volume 7 | Article 2781
REVIEW
published: 22 July 2016
doi: 10.3389/fimmu.2016.00278
Frontiers in Immunology | www.frontiersin.org
Edited by:
Nurit Hollander,
Tel Aviv University, Israel
Reviewed by:
Robert Weissert,
University of Regensburg, Germany
Helmut Jonuleit,
University of Mainz, Germany
*Correspondence:
Azzam A. Maghazachi
amagazachi@sharjah.ac.ae
Specialty section:
This article was submitted to
Immunotherapies and Vaccines,
a section of the journal
Frontiers in Immunology
Received: 30May2016
Accepted: 06July2016
Published: 22July2016
Citation:
Al-JaderiZ and MaghazachiAA
(2016) Utilization of Dimethyl
Fumarate and Related Molecules for
Treatment of Multiple Sclerosis,
Cancer, and Other Diseases.
Front. Immunol. 7:278.
doi: 10.3389/fimmu.2016.00278
Utilization of Dimethyl Fumarate and
Related Molecules for Treatment of
Multiple Sclerosis, Cancer, and Other
Diseases
Zaidoon Al-Jaderi and Azzam A. Maghazachi*
Department of Clinical Sciences, College of Medicine and Sahrjah Institute for Medical Research, University of Sharjah,
Sharjah, United Arab Emirates
Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl
fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be potent
with less side effects than several other drugs. On the other hand, monomethyl fumarate
(MMF), a related compound, has not been examined in greater details although it has
the potential as a therapeutic drug for MS and other diseases. The mechanism of action
of DMF or MMF is related to their ability to enhance the antioxidant pathways and to
inhibit reactive oxygen species. However, other mechanisms have also been described,
which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is
also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast
cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage,
osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article, we will touch on
some of these diseases with an emphasis on the effects of DMF and MMF on various
immune cells.
Keywords: NK cells, dimethyl fumarate, cancer, multiple sclerosis, monomethyl fumarate
INTRODUCTION
Twenty years ago, there was no treatment for multiple sclerosis (MS). Today, there are wide varieties
of immunomodulatory drugs, which have been licensed to treat MS patients. For relapsing-remitting
MS (RRMS) patients, several drugs have been approved. During the 1990s, beta interferon and
glatiramer acetate were the only drugs available. Other drugs, such as natalizumab, teriunomide,
and ngolimod, were later approved. ese drugs modify the immune system to slow disease pro-
gression, decrease attacks, and reduce the development of new brain lesions.
Dimethyl fumarate (DMF) has been lately approved by the US Food and Drug Administration
(FDA) as an oral drug for MS patients. is drug was rst used to treat inammatory skin diseases,
such as psoriasis. e benecial eects of this medication corroborated with regulating CD4+ 1
cell dierentiation. In clinical trials, it showed positive benets for MS patients by lowering risk of
relapse and reducing the number of brain lesions (1–6).
e mechanism of action is not fully known. Aer oral intake, DMF is completely absorbed in the
small intestine, and only small amounts are excreted in the feces and urine (7). DMF possesses a short
half-life of ~12min inside the body (8). Aer absorption, DMF is rapidly hydrolyzed by esterases
to monomethyl fumarate (MMF) (9), which has a short half-life of 36h. is molecule interacts

FIGURE 1 | Chemical structures of DMF and MMF. Also shown is the structure of fumaric acid, the precursor molecule.
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with the immune cells in the blood circulation and crosses the
blood–brain barrier (BBB) to the central nervous system (CNS)
(10). Figure1 shows the structures of DMF and MMF.
Dimethyl fumarate is an α, β-unsaturated carboxylic acid
ester. It is demonstrated that DMF by activating nuclear factor
erythroid 2-related factor (Nrf2), stimulated the production of
glutathione (GSH), the cells most important scavenger of reac-
tive oxygen species (ROS) (11), hence, protecting against ROS-
induced cytotoxicity. Further studies demonstrate that DMF
downregulated nuclear factor kappa B (NF-κB) in cells, inhibited
the anti-apoptotic protein Bcl-2, and induced apoptosis. Cells
challenged with oxidative stressors increase their antioxidant
capacity as a response to increase ROS production and maintain
homeostasis. Nrf2 acts as a key control of the redox gene tran-
scription; under oxidative stress, the Nrf2 signaling is activated
to enhance the expression of a large number of antioxidants and
enzymes that restore redox homeostasis. Nrf2 interacts with
the cysteine-rich protein Kelch-like ECH-associated protein 1
(Keap1) and acts as an adaptor protein for the Cul3-dependent
E3 (Cul3) ubiquitin ligase complex. In normal conditions, Keap1
promotes ubiquitination and repeatedly eliminates Nrf2 within
a half-life of 13–21min (12, 13). Keap1 possesses many cysteine
residues in the amino acid terminal that act as sensors detecting
changes in cellular redox state. During cellular stress, Keap1 is less
eective at promoting Nrf2 degradation (12, 14).
Under normal conditions, Nrf2 is sequestered in the cytoplasm
via binding to its inhibitory molecule Keap1. ROS/stress causes
dissociation of Nrf2-Keap1 complex, leading to activation of Nrf2
and its translocation into the nucleus. In the nucleus, Nrf2 het-
erodimerizes with other transcription factors, such as MAF, and
consequently, binds the antioxidant responsive elements (ARE)
in the target genes. Nrf2 promotes transcriptional activation of
antioxidants and detoxifying enzymes. At the same time, phos-
phorylation of the repressor molecule IκB by ROS/stress causes
activation of NF-κB, leading to activating gene transcription
encoding inammatory mediators. Studies have shown that Nrf2
and NF-κB pathways have inhibitory inuence on one another.
EFFECTS OF DMF ON THE INNATE
IMMUNE SYSTEM
e main components of the innate immune system are epithelial
barriers, leukocytes, dendritic cells (DCs), and natural killer (NK)
cells. NK cells are large granular lymphocytes that spontaneously
lyse target cells and are important for defending against viral
infections as well as controlling tumor growth. NK cells have also
immunoregulatory role by secretion of cytokines, chemokines,
as well as cell-to-cell cross-talk (15). ese cells express several
activating and inhibitory receptors that detect target cells and
control NK cell activity. In human, NK cells are divided by the
expression of CD56 molecule into CD56dim and CD56bright subsets
(15, 16).
e ow cytometric analysis of peripheral blood immune
cells in 41 DMF-treated MS patients shows that these patients
had signicantly fewer circulating CD8+ T cells, CD4+ T cells,
CD56dim NK cells, CD19+ B cells, and plasmacytoid DCs (17).
Furthermore, the expression of CXCR3+ (a potential marker for
1) and CCR6+ (a potential marker for 17) was reduced,
while the number of regulatory T cells (Treg) was unchanged.
Interestingly, DMF did not aect circulating CD56bright NK cells,
CD14+ monocytes, or myeloid DCs. However, DMF-treated
patients had signicantly fewer CD56dim NK cells when compared
with healthy controls (17). A clinical study of 35 RRMS patients
at baseline, 3months, 6months, and 12months aer initiation
of DMF treatment shows that total leukocyte and lymphocyte
counts diminished aer 6months, whereas aer 12months of
DMF therapy total T cells counts decreased by 44%, CD8+ T cell

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counts declined by 54.6%, and CD4+ T cell counts decreased by
39% (18). CD19+ B cell counts were also reduced by 37.5%, and
eosinophils counts were decreased by 54%, whereas the percent-
ages of neutrophils, monocytes, basophils, and NK cells were not
signicantly altered (18).
It has been previously demonstrated that MMF is a potent
agonist of hydroxycarboxylic acid receptor 2 “(HCA2), a G
protein coupled receptor also known as GPR109A” (19). It is
reported that HCA2 mediates the therapeutic eects of DMF or
MMF in experimental autoimmune encephalomyelitis (EAE)
mouse model (20). Recently, we observed that MMF enhanced
primary non-activated human CD56+ NK cell lysis of leukemic
cell line K562 and B-cell lymphoma RAJI cells in vitro (21).
Furthermore, MMF upregulated NKp46 expression on the
surface of CD56+ NK cells, an activity correlated with upregula-
tion of CD107a expression and the release of Granzyme B from
CD56+ NK cells (21).
Moreover, MMF delayed EAE clinical score in SJL/J mice and
prevented the disease progression in treated mice. ese results
are linked to enhanced NK cells lysis of DCs isolated from the
same mice (22). To correlate these ndings with human settings,
we recently observed that human NK cells incubated with various
concentrations of DMF or MMF robustly lysed immature DCs
in vitro (manuscript in preparation). ese ndings suggest
that one mechanism of action for these “drugs” is plausibly due
to activating NK cells to lyse DCs, and consequently, impeding
antigen presentation to autoreactive T cells.
Dendritic cells represent key links between the innate and
adaptive immune system (23). T cells and NK cells are stimulated
through direct contact with activated DCs (24). DCs play a major
role in regulating the immune response by releasing cytokines
and expressing co-stimulatory molecules. ey are capable
of processing both exogenous and endogenous antigens and
present them in the context of MHC class I or II molecules. It
has been reported that DMF inhibited DCs maturation through
a reduction in the release of the inammatory cytokines IL-6
and IL-12. Furthermore, DMF activated type II DCs, which have
anti-inammatory eects and suppressed type I DCs, which are
inammatory (25, 26). DMF induced type II DCs by regulating
GSH depletion, followed by increased heme oxygenase-1 (HO-1)
expression and suppressing STAT1 phosphorylation in DCs (26).
is, combined with the reduction in the inammatory cytokines
by nuclear translocation of NF-κB, resulted in inhibiting CD1a,
CD40, CD80, CD86, and HLA-DR expression (27). Consequently,
the capacity of DCs to stimulate allogeneic 1 and 17 cells is
reduced. It was also determined that increased production of the
2 cytokines and increased expression of IL-10, instead of IL-12
and IL-23 by DCs, enhanced the development of T regulatory
(Treg) cells (28).
We reported that monocyte-derived DCs isolated from
EAE mice treated with MMF did not increase the expression of
CD80 molecule (22). Interestingly, E-cadherin expression was
upregulated in EAE mice, and MMF reversed this upregula-
tion. Increased E-cadherin expression suggests a shiing of
the immune system toward inammatory 1/17 response.
ese results support previous study showing that inammatory
E-cadherin+ bone marrow-derived DCs isolated from animals
with colitis promoted 17 response (29). e study also dem-
onstrates that E-cadherin+ DCs enhanced 1 cell responses (29).
Furthermore, E-cadherin+ DCs increased the number of IFN-γ+
CD4+ T cells and decreased the number of IL-4+ CD4+ T cells
(30). MMF by decreasing E-cadherin expression on DCs may
decrease inammatory 1/17 proliferation and may enhance
the anti-inammatory 2 cells.
Although DMF but not MMF induced apoptosis in iDCs and
moderately inhibited the ability of DCs to induce proliferation of
allogeneic T cells, it is reported that MMF aected the polariza-
tion but not maturation of monocyte-derived DCs, resulting in
downregulating 1 lymphocyte responses (31). In vitro study
for the eects of MMF on DCs dierentiation shows that MMF
inhibited monocyte-derived DCs dierentiation in response to
LPS, resulting in cells that are incapable of appropriately mature
to DCs. In addition, MMF did not decrease the capacity of DCs to
capture antigens, but MMF/DCs interaction resulted in produc-
ing low levels of IL-12, IL-10, and TNF-α, whereas IL-8 produc-
tion was not altered (32). Consequently, MMF/DCs interaction
partially aected IFN-γ production by naive T cells, whereas the
production of IL-4 and IL-10 was not inuenced by MMF (32).
Another study demonstrates that DMF inhibited DCs matura-
tion by reducing the production of the inammatory cytokines
IL-6 and IL-12 as well as the expression of MHC class II, CD80,
and CD86 (27). Furthermore, immature DCs activated fewer
Tcells characterized by low IFN-γ and IL-17 production (27).
In contrast, de Jong etal. (33) demonstrate that MMF increased
the production of IL-4 and IL-5 without altering the production
of IL-2 and interferon-γ in stimulated peripheral blood mononu-
clear cells challenged with bacterial antigens.
TREATMENT OF PSORIASIS AND OTHER
SKIN DISEASES WITH DMF
Psoriasis is a type-1 cytokine-mediated chronic autoimmune skin
disease aided by the inltration of 1/17 cells into the skin
(34–36). DMF is utilized to treat psoriasis in European countries
for more than 30years. Fumaric acid was rst used for treatment
of psoriasis by the German chemist Walter Schweckendiek in
1959. In 1994, DMF was licensed in Germany under the trade
name Fumaderm for the treatment of psoriasis. DMF inhibited
Janus kinas (JAK) signaling and interfered with intracellular
proteins tracking and consequently, inhibited the release of
pro-inammatory cytokines, such as IL-12, IL-23, and TNF,
whereas the release of anti-inammatory cytokines, such as
IL-10, was increased. DMF also inhibited the production of IFN-
γ and enhanced the production of IL-10 in the culture of psoriatic
keratinocytes (37).
Previous experimental and clinical studies were focused on
the mechanism of action for DMF that could aect the immune
system. e immunohistochemical studies of psoriatic plaques
indicate that DMF has several anti-inammatory eects via a
number of pathways, leading to reduction in the levels of several
inammatory T cell subsets (38, 39) and decreased recruitment

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of inammatory cells (40). e ability of DMF or MMF to induce
apoptosis of CD4+ and CD8+ T cells and in vitro switching the
immune system toward a 2 anti-inammatory type response in
psoriasis patients could be through impaired DCs maturation and
induction of apoptosis. In addition, DMF inhibited the formation
of new blood vessels, a process that is involved in the formation
of psoriatic plaques (41).
Clinical studies demonstrate that DMF reduced CD4+ T cells
and CD8+ T cells by inducing apoptotic cell death (42). In vivo
studies indicate that DMF inhibited T cell mediated organ rejec-
tion in a rat model (43). A study of allergic contact dermatitis,
a skin disorder in which an exaggerated T cell response occurs,
shows that DMF suppressed allergen-induced T cell proliferation,
corroborated with modulating cytokines/chemokines expression
by reducing the levels of IFN-γ but not IL-5 and downregulating
CXCR3 but not CCR4 expression (44).
TREATMENT OF MULTIPLE SCLEROSIS
PATIENTS WITH DMF
Multiple sclerosis is a chronic inammatory autoimmune
disease of the CNS in which the insulating myelin sheaths of
nerve cell axons in the brain and spinal cord are attacked by the
immune system (45). e principal mechanism responsible for
this disease is still incompletely understood. e consensus is
that activated T cells attack oligodendrocytes, leading to destruc-
tion of myelin sheaths (demyelination). Furthermore, the pres-
ence of inammatory T cells in the CNS triggers recruitment
of more T cells, Bcells, dendritic cells, microglia cells, and NK
cells (46). Due to the progressive neurodegenerative nature of
MS, therapeutic modalities that exhibit direct neuroprotective
eects are needed. A phase 3 clinical trial study of 2667 RRMS
patients demonstrates the ecacy and safety of DMF in MS (1).
In vitro study indicates that DMF increased the frequency of the
multipotent neurospheres resulting in the survival of mouse and
rat neural stem progenitor cells (NPCs) following oxidative stress
with hydrogen peroxide (H2O2) treatment (47). Using motor
neuron survival assay, DMF signicantly promoted survival
of motor neurons under oxidative stress. Furthermore, DMF
increased the expression of Nrf2 at both RNA and protein levels
in the NPC cultures (47).
ere is agreement that antioxidants reduce the risk of certain
pathological conditions, such as neurodegenerative diseases.
Invivo animal studies have shown that DMF or MMF inhibited
the disease course in the EAE model (48). It is also demonstrated
that MMF crossed the BBB, indicating it may have a direct
cytoprotective function in the CNS (49). e detoxication
capabilities of DMF or MMF reduced the production and release
of inammatory molecules, such as TNF-α, IL-1β, and IL-6 as
well as nitric oxide from microglia and astrocytes activated with
LPS in v itro (50, 51). DMF or MMF increased the production
of detoxication enzymes, such as nicotinamide adenine dinu-
cleotide phosphate quinone reductase 1 (NQO-1), HO-1, and
cellular glutathione, abolishing NF-kB translocation into the
nucleus (52). NQO-1 is also detected in the liver and in the CNS
of DMF-treated animals. is results in decreased expression of
NF-kB-dependent genes that regulate the expression of inam-
matory cytokines, chemokines, and adhesion molecules, and
consequently, reduced the damage to CNS cells. Reducing the
expression of adhesion molecules in the BBB represents a critical
step in the transmigration of immune cells into the CNS. DMF
inhibited TNF-α-induced expression of intracellular adhesion
molecule-1 (ICAM-1), E selection, and the vascular cell adhe-
sions molecule-1 (VCAM-1) in endothelial cells invitro (53, 54).
is is correlated with activating Nrf2 (55–58), which is released
from the Keap-1complex via the activity of fumarates (see above).
is may lead to reducing free radicals, preventing the synthesis
of reactive nitrogen species, and thus protecting the CNS from
degeneration and axonal loss (59, 60). ese immunomodulatory
activities of DMF or MMF, which constitute inhibiting cytokine
production and nitric oxide synthesis, are important for the
protection of oligodendrocytes against ROS-induced cytotoxicity
and consequently, oligodendrocytes survival during an oxidative
attack is augmented.
Multiple sclerosis animal models, such as EAE, are induced by
immunization with dierent myelin antigens, such as proteolipid
peptide (PLP139–151) in SJL/J mice, an animal model disease that
may represent relapsing-remitting form of MS, or C57BL/6J mice
immunized with MOG35–55, a model closely resembles chronic
progressive MS. ese models are characterized by inammation,
demyelination, and axonal lose. Treatment of EAE mice with
DMF reduced macrophage-induced inammation in the spinal
cord (48). DMF suppressed 1 and 17 cell dierentiation as
well as expression of pro-inammatory cytokines IFN-γ, TNF-α,
and IL-17 (61). e drug also promoted 2 cells that produce
IL-4, IL-5, and IL-10 (33). In chronic MS, microglia cells are
activated and released pro-inammatory cytokines and stress-
associated molecules leading to neurodegeneration and alteration
of synaptic transmission (62). Modulation of microglia activation
toward an alternatively activated phenotype can modify the out-
come of some experimental models of neurological diseases. e
study on EAE demonstrates that exposure to MMF switched the
molecular and functional phenotype of activated microglia from
pro-inammatory type to neuroprotective eect (49). is switch
in activity may occur through activation of HCAR2. MMF bind-
ing to HCAR2 triggered a pathway driven by the AMPK/Sirt axis
resulting in inhibition of NF-κB and reducing pro-inammatory
cytokine production (49).
EFFECTS OF DMF ON THE CENTRAL
NERVOUS SYSTEM
A recent study reports that administration of DMF protected
claudin-5 expression in the BBB along with reduced brain edema
formation in C57BL/6 mice undergoing experimental ischemia
reperfusion injury (63). Using the immortalized murine brain
endothelial cell line bEND.3, a preservation of zonula occludens-1
(ZO-1) and VE-cadherin localization in oxygen–glucose deprived
cells in the presence of DMF was observed. Reduced transen-
dothelial migration of the human monocyte cell line THP-1
toward CCL2 chemokine in the lower chamber of a transwell
system aer pretreatment of the bEND.3 cells with DMF was also

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noted. Further observations demonstrate decreased ICAM-1,
VCAM-1, and E-selectin mRNA expression in bEND.3 cells aer
treatment with DMF for 6h (54).
In vitro human umbilical vein endothelium examination
indicates that DMF or MMF modulated pro-inammatory
intracellular signaling and T-cell adhesiveness of human brain
microvascular endothelial cells (64). Neither DMF nor MMF
reduced the basal expression of ICAM-1 under inammatory
condition or blocked NF-κB in human brain microvascular
endothelial cells compared to solvent control. Hence, it is sug-
gested that brain endothelial cells do not directly mediate a
potential blocking eect of fumaric acid esters on the inltration
of inammatory T cells into the CNS (64). It is also determined
that DMF ameliorated inammation, reduced BBB permeability
and improved neurological outcomes by casein kinase 2 and Nrf2
signaling pathways in experimental intracerebral hemorrhage
(ICH) mouse model (65).
Evidence from clinical and animal studies suggests that
inammation and oxidative stress, which occur aer hematoma
formation, are involved in ICH-induced secondary brain injury
and neurological dysfunction (66). VCAM-1 and ICAM-1 are
adhesion molecules expressed in the endothelium important dur-
ing inammation and aer tissue injury. Both are increased upon
activation of NF-κB-mediated TNF-α signaling pathway. TNF-α
increases early onset endothelial adhesion by protein kinase
C-dependent upregulation of ICAM-1 expression, which exacer-
bates ICH. Investigating the experimental autoimmune neuritis
indicates that DMF treatment reduced the neurological decits by
ameliorating inammatory cell inltration and demyelination of
sciatic nerves. In addition, DMF treatment decreased the level of
pro-inammatory M1 macrophages, while increasing the number
of anti-inammatory M2 macrophages in the spleens and sciatic
nerves of EAN rats (67, 68). In RAW 264.7 macrophage cell line,
a shi in macrophage polarization from M1 to M2 phenotype
was demonstrated to be dependent on DMF application. In sciatic
nerves, DMF treatment elevated the level of Nrf2 and its target
HO-1, which may facilitate macrophage polarization toward M2
type (68). In addition, by reducing NF-kB in astrocytes, DMF
inhibited the degradation of IkBa and reduced the expression
of nitric oxide synthase (69). Moreover, DMF improved the
inammatory milieu in the spleens of EAN rats, characterized by
downregulating mRNA for IFN-γ, TNF-α, IL-6, and IL-17 and
upregulating mRNA level for IL-4 and IL-10 (68).
EFFECTS OF DMF ON TUMOR
DEVELOPMENT
It has been reported that fumarase is involved in DNA repair
(70). By studying yeast cells, it is observed that cytosolic fumarase
plays a role in detecting and repairing DNA damage, particularly
double-stranded DNA breaks. According to this theory, if the
cells lack the fumarase, they may need to repair damaged DNA
and are most likely prone to develop tumors. Further study on
the role of redox demonstrates that high levels of ROS are harm-
ful to normal cells and may lead to development of tumor by
inducing DNA damage. Malignant transformation also increases
cellular stress, leading to high ROS levels. On the other hand,
Keap1-Nrf2 system protects cells from the eects of oxidants by
regulating the expression of cytoprotective proteins (71). In vivo
evidence indicates that Nrf2 has a protective role against tumor
development in mouse models and in prostate cancer in humans
(72). e mechanism by which Nrf2 is protective against tumor
development has been attributed to the ability of Nrf2 to reduce
the amount of ROS and DNA damages in cells.
It has also been demonstrated that DMF inhibited the prolif-
eration of A375 and M24met cell lines and reduced melanoma
growth and metastasis in experimental melanoma mouse models
(73). Furthermore, DMF arrested the cell cycle at the G2-M
boundary and was pro-apoptotic, inhibiting tumor cell growth.
On the other hand, MMF increased primary human CD56+
NK cell lysis of K562 and RAJI tumor cells, suggesting that this
molecule may have insitu antitumor activity (21).
ROLE OF DMF IN GASTROINTESTINAL
ULCERATION
It has been demonstrated that stress can play a pathogenic role
for gastrointestinal ulceration, by disrupting gastric mucosal
defensive barrier (74). Activators of stress give rise to the release
of corticotropin-releasing hormone (CRH). CRH acts on the
pituitary gland and stimulates the secretion of ACTH, which
promotes glucocorticoids release from the adrenal cortex (75).
Glucocorticoids not only interfere with tissue repair, elevate levels
of gastric acids, and pepsin but also reduce the secretion of gastric
mucus and eventually impair gastric mucosal barrier resulting in
peptic ulcer. Low daily oral doses of MMF may prevent the chronic
foot-shock stress-induced gastric ulcers and may associate with dif-
ferential hormonal and oxidative processes (76). MMF suppressed
the stress-induced elevation in adrenal gland corticosterone level
and modulated the oxidative stress responses. Interestingly, DMF
did not inhibit the eect of innate defense against microorgan-
ism. Treatment of monocytes and neutrophils with DMF aer
stimulation with Staphylococcus aureus, Escherichia coli, or the
yeast Candida albicans in addition to zymosan particles or the
tripeptide fMLP resulted in increased production of superoxide
anion, which exerts anti-microbial eects (77).
EFFECTS OF DMF ON COLLAGEN
TYPE II DEGRADATION
In vivo study of collagen type II degradation suggests that DMF
ameliorated the disease by inhibiting the expression of metallo-
proteinase (MMP)-1, MMP-3, and MMP-13 that are induced by
TNF-α (78). DMF may attenuate MMPs expression by suppress-
ing JAK1 and JAK2/STAT3 pathways and by blocking TNF-α-
induced STAT3 phosphorylation and DNA-binding activity (79).
In vivo mice study on renal brosis, where TGF-β plays a key role
in the development of the disease, demonstrates that DMF treat-
ment may prevent renal brosis via Nrf2-mediated suppression
of TGF-β signaling (80).

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CONCLUSION AND FUTURE DIRECTIONS
Dimethyl fumarate was originally used for treatment of psoriasis.
Its success in treating RRMS patients led for its approval as an
oral drug to treat MS patients. One mechanism of action that our
group pursued is that DMF might enhance natural killer cell lysis
of dendritic cells, hence, impeding presenting encephalitogen to
autoreactive T cells. Further investigations suggest that DMF
may also be used in the oncology eld due to its ability to sup-
press the growth of melanoma cells. On the other hand, it appears
that related molecules, such as MMF, may have even more potent
antitumor activity than DMF. Although the association among
DMF and MMF is at present conjectural, it is documented that
MMF has robust antitumor activity by activating natural killer
cells to kill tumor cells. is new mechanism of action for MMF
should provide imputes for investigating this molecule not
only as a therapeutic tool for autoimmune diseases but also for
cancer and immunodecient diseases. Tab l e  1 shows the current
knowledge regarding the eects of DMF and MMF on various
immune cells.
AUTHOR CONTRIBUTIONS
Both authors contributed to writing this review article.
TABLE 1 | Immunoregulatory effects of DMF and/or MMF on various immune cells.
Cell type Molecule Cytokine/other molecules involved Effect(s) Reference
T cells DMF/MMF ↓IFN-γ, ↓TNF-α, ↓IL-17, ↑IL-4, ↑IL-5, ↑IL-10, ↓CXCR3,
↓CCR6
↓Bcl-2, ↑Apoptosis, ↓Th1, ↓Th17, ↑Th2, ↓CD4, ↓CD8,
↑Tre g
(17, 18, 27, 32,
42, 44, 61)
B cells DMF ↑Nrf2→↑GSH→↓ROS, ↓NF-kB ↓Bcl-2, ↑Apoptosis, ↓CD19 B cells (17, 18)
Monocytes DMF ↑Nrf2, ↓NF-kB No effect on cell numbers, ↑Antioxidant response (18, 77)
DCs DMF/MMF ↓GSH→↑HO-1, ↓NF-kB, ↓IL-6, ↓IL-12, ↑IL-10, ↓TNF-α↓,
E-cadherin
↑Apoptosis, ↓plasmacytoid DCs, ↓DC maturation, ↓type I
DCs, ↑type II DCs
(17, 22, 25–27,
31, 32)
NK cells DMF/MMF ↑NKp46, ↑CD107, ↑Granzyme B ↓CD56dim NK cells, No effect on CD56bright numbers,
↑CD56bright NK cells lysis of tumor cells, ↑Lysis of DCS
(17, 18, 21, 22)
Macrophages DMF ↑Nrf2, ↓mRNA of IFN-γ, ↓mRNA of TNF-α, ↓mRNA of IL-6,
↓mRNA of IL-17, ↑mRNA of IL-4, ↑mRNA of IL-10
↓M1 macrophages, ↑M2 macrophages (68)
Neutrophils DMF/MMF ↓HCA2 ↓Number of infiltrating neutrophils (20)
Keratinocytes DMF ↓IL-12, ↓IL-23, ↓TNF, ↓IFN-γ, ↑IL-10, ↓IL-6, ↓TGF-α ↓Proliferation of keratinocytes (37)
Endothelial cells DMF ↓TNF-α, ↓ICAM-1, ↓VCAM-1, ↓E-selection, ↑Nrf2 ↓BBB permeability→↓Immune cell migration (41, 54, 55, 65)
Microglia DMF/MMF ↓IL-1, ↓IL-6, ↓TNF-α, ↓NO, ↑Nrf2→↑GSH→↓ROS,
↓NF-kB, ↑NQO-1, ↑HO-1, ↑HCAR2
↑Antioxidant response, switching activated microglia from
pro-inflammatory to neuroprotective
(49, 50, 52)
Astrocytes DMF/MMF ↑Nrf2→↑GSH→↓ROS, ↓NF-kB, ↓IL-1, ↓IL-6, ↓TNF-α, ↓NO ↑Antioxidant response (50, 52, 58)
Neurons DMF ↑Nrf2→↑GSH→↓ROS ↓Apoptosis, ↑Neurons survival under oxidative stress (47, 58)
Tumor cells DMF Arrest the cell cycle at G2-M, ↓pro-apoptotic ↓Proliferation of melanoma cells, ↓Proliferation of tumor
cells, ↑Apoptosis
(73)
↓, decreased; ↑, increased.
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