Cytokine and Growth Factor Reviews 44 (2018) 18–27

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Cytokine and Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

Potential roles of IL-1 subfamily members in glycolysis in disease T

a,1 a,1 a,1 a b c
Qi Tan , Qi Huang , Yan Ling Ma , KaiMin Mao , GuangHai Yang , Ping Luo ,
GuanZhou Maa, PeiYuan Meib, Yang Jina,
⁎

a
Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, 430022, China
b
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
c
Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

ARTICLE INFO ABSTRACT

Keywords: The interleukin-(IL)-1 subfamily consists of IL-1α, IL-1β, IL-1 receptor antagonist IL-1Ra and IL-33. These cy-
IL-1α tokines are the main members of the IL-1 family and have been widely recognized as having significant roles in
IL-1β pro-inflammatory and immunomodulatory actions. Mounting evidence has revealed that these cytokines also
IL-1Ra play key roles in the regulation of glycolysis, which is an important metabolic pathway in most organisms that
IL-33
provides energy. Dysregulation of glycolysis is associated with various diseases, including type 2 diabetes,
Glycolysis
rheumatoid arthritis (RA) and cancer. We reviewed studies addressing the important roles of IL-1 subfamily
Metabolism
cytokines, with particular focus on their ability to regulate glycolysis in disease states. In this review, we
summarize the potential roles of IL-1 subfamily members in glycolysis in disease states and address the un-
derlying mechanisms. Furthermore, we discuss the potential of these cytokines as therapeutic targets in clinical
applications to provide insight into possible therapeutic strategies for treatment, especially for cancers.

1. Introduction major regulators, playing active roles in pro-inflammatory and im-

Interleukin (IL) was first described in studies on fever pathogenesis
by Menkin and Beeson in 1943–1948, and it functions as a major reg-
ulator of responses to infections or sterile insults [1]. Subsequent stu-
dies on the origin and function of this regulator led to the name “in-
terleukin,” which was used to describe the soluble factors secreted by
macrophages and lymphocytes. Thus, IL-1 was used to describe the
macrophage product [2]. Subsequent research has revealed that IL-1 is
a product not only of macrophages but also of neutrophils, dendritic
cells and NK cells [3]. At present, the IL-1 family consists of 12 cyto-
kines (IL-1α, IL-1β, IL-1Ra, IL-33, IL-18, IL-18BP, IL-37, IL-36α, IL-36β,
IL-36γ, IL-36Ra and IL-38). These cytokines have similar gene struc-
tures and exert their biological properties via binding to specific
membrane receptors such as intracellular Toll/IL-1 receptor (TIR) do-
mains or extracellular immunoglobulin-like binding domains on target
cells [4]. Furthermore, according to the lengths of their precursors,
these cytokines can be classified into three subfamilies [1]: the IL-1
subfamily (IL-1α, IL-1β, IL-1Ra, IL-33) [2], the IL-18 subfamily (IL-18,
IL-18BP, IL-37) and [3] the IL-36 subfamily (IL-36α, IL-36β, IL-36γ, IL-
36Ra, IL-38) [4,5]. Members of the IL-1 family are well recognized as
munomodulatory actions and include mainly the IL-1 subfamily cyto-
kines, which were the first IL-1 cytokines discovered and have been
widely studied since [6]. Recent research has revealed that IL-1 sub-
family cytokines are involved in the pathogenesis of several diseases,
including type 2 diabetes [7], rheumatoid arthritis (RA) [8] and cancer
[9], through directly or indirectly targeting the process of glycolysis,
which is an important metabolic pathway for providing energy in most
organisms [10]. This phenomenon was first reported by Taylor and
coworkers in 1988; in their study, IL-1α and IL-1β were implicated in
the increased glycolysis of rheumatoid synovial cells in RA [8]. Sub-
sequently, these authors obtained consistent results with human dermal
fibroblasts (HDF) from familial adenopolyposis (FAP) of the colon and
severe sepsis states in vitro, which suggested that the changes in gly-
colysis induced by these two cytokines were the molecular mechanisms
underlying the disease, a possibility warranting further study [11,12].
Since those studies, many experiments have been conducted to in-
vestigate the roles of the IL-1 subfamily in glycolysis. In this review, we
summarize the major research on the regulation of glycolysis by IL-1
subfamily members and discuss the underlying mechanisms that result
in disease.

Corresponding author.
⁎

E-mail addresses: m201775412@hust.edu.cn (Q. Tan), huangqi66@126.com (Q. Huang), mayanling811@hust.edu.cn (Y.L. Ma), 444931158@qq.com (K. Mao),
2004XH0838@hust.edu.cn (G. Yang), 985066021@qq.com (P. Luo), 837324889@qq.com (G. Ma), M13260630812@163.com (P. Mei), whuhjy@126.com (Y. Jin).
1
Qi Tan, Qi Huang and YanLing Ma contributed equally to this work.

https://doi.org/10.1016/j.cytogfr.2018.11.001
Received 4 November 2018; Received in revised form 8 November 2018; Accepted 12 November 2018
Available online 16 November 2018
1359-6101/ © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Q. Tan et al.
Glycolysis, which was first clearly described by Meyerhof et al in the
1940s, is usually defined as the conversion of glucose to lactate with the
synthesis of adenosine triphosphate (ATP) under anaerobic conditions
[10,13]. Although glycolysis is a low-efficiency process that produces 2
ATP molecules from 1 molecule of glucose, it can synthesize ATP ra-
pidly. Accordingly, it plays an essential role in providing energy for
most organisms, especially for metabolically active cells such as cancer
cells [14]. Under aerobic conditions, glycolysis is necessary for the
survival and growth of cancer cells. Accumulating evidence suggests
that cancer cells prefer to synthesize ATP through glycolysis even when
there is a sufficient oxygen supply. This phenomenon was first de-
scribed by Otto Warburg in the 1920s; thus, “aerobic glycolysis” is also
known as “the Warburg effect” [15]. In general, glycolysis plays pivotal
roles in energy production and cell proliferation. It has been reported
that the dysregulation of glycolysis is responsible for various human
diseases, such as type 2 diabetes, RA and cancer. Evidence that this
dysregulation can result in disease comprises the following [1]: De-
creased glucose utilization in pancreatic islets leads to type 2 diabetes
mellitus [7,2]. Increased levels of lactate, which is the product of gly-
colysis in the rheumatoid joint, are associated with RA [8,3]. Lactate
acts as the most important energy source for cancer cells, and inhibiting
glycolysis can inhibit tumor growth [9]. Understanding the mechanisms
of glycolysis dysregulation can lead to the development of novel ther-
apeutic strategies for treating disease. Several studies have identified
correlations between the levels of regulating factors, including those of
the IL-1 subfamily, and the dysregulation of glycolysis. Therefore, the
present review focuses in particular on the roles of IL-1 subfamily
members in glycolysis and their potentials as therapeutic targets for
treating associated diseases.
2. Biological features of cytokines in the IL-1 subfamily
2.1. IL-1α
IL-1α (IL-1F1) is one of most studied members of the IL-1 subfamily
due to its multiple effects and the fact that it was the first member
discovered [16]. IL-1α is constitutively expressed in many types of cells
under normal conditions, especially in epithelial cells, and its precursor
is synthesized and stored in the cytoplasm. The conversion of pro-IL-1α
to a mature 17-kDa protein requires a Ca2+-activated protease, calpain
[17]. However, both forms of IL-1α are fully active and are released
from intracellular to extracellular space under necrosis or pyroptosis. As
a result, IL-1α in the extracellular space is an indicator of cell stress due
to infection, injury or hypoxia. Accordingly, IL-1α is used as a damage-
associated molecular pattern molecule for danger signals involved in
inflammatory responses [18,19]. Following the release of IL-1α, its
function is exerted primarily through IL-1 receptor type 1 (IL-1R1). For
signaling to occur, the activation of signal transduction of IL-1/IL-1RI
complexes is necessary, which requires the IL-1 receptor accessory
protein (IL-1RAcP). IL-1RAcP functions as a coreceptor and is recruited
when IL-1α binds to IL-1R1. Interestingly, IL-1RAcP is also necessary
for IL-1β and IL-33 (see below) [20]. IL-1α binding causes the assem-
bling of signaling modules, which are formed by IL-1, IL-1RI, IL-1RAcP,
myeloid differentiation primary response gene 88 (MYD88) and IL-1
receptor–activated protein kinase (IRAK)-4. Through the phosphoryla-
tion of IRAK-4, IRAK-1 and IRAK-2 are activated; this activation is as-
sociated with the recruitment of tumor necrosis factor–associated factor
6 (TRAF6). TRAF6 activates two pathways. One pathway signals
through mitogen-activated protein kinase (MAPK) to trigger the acti-
vation of P38, c-Jun N-terminal kinases (JNKs), extracellular signal-
regulated kinases (ERKs) and activator protein 1 (AP-1), and the other
pathway leads to the activation of nuclear factor κB (NF-κB) tran-
scription factors [21,22]. IL-1α also signals through mitogen-activated
phosphatidylinositol-3-phosphate (PI3K), which functions as a med-
iator of glycolysis (see below), to activate NF-κB and thereby induce
gene expression, including the expression of IL-6 and IL-8, which is
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Cytokine and Growth Factor Reviews 44 (2018) 18–27
associated with inflammatory factor production and immune regulation
[23]. Accordingly, a major property of IL-1α is the mediation of the
early phases of sterile inflammation and the T helper (Th) 17 response.
In addition, IL-1α has been demonstrated to play a role in the nucleus
by stimulating transcription.
2.2. IL-1β
IL-1β (IL-1F2) is another member of IL-1 subfamily. It has biological
properties similar to those of IL-1α due to its binding to the same re-
ceptor, IL-1R1. IL-1β can also activate NF-κB and AP-1 through the
IRAK pathway and activates the PI3K pathway leading to NF-κB acti-
vation. Accumulating evidence indicates that the PI3K/protein kinase B
(Akt)/mammalian target of rapamycin (mTOR) signaling pathway,
which is recognized as a regulatory pathway in glycolysis (described
below), is involved in IL-1β-dependent signal transduction [24]. How-
ever, unlike IL-1α, IL-1β is only expressed by a small number of cell
types including monocytes, macrophages and dendritic cells. In addi-
tion, the IL-1β precursor is not active, and its synthesis requires the
induction of transcription factor NF-κB after the stimulation of innate
immune cells, such as macrophages and dendritic cells. The synthesis of
IL-1β precursor can also be regulated by tumor necrosis factor-alpha
(TNFα), IL-18 or itself [25]. However, to increase the potency of the
final product, the IL-1β precursor has to be cleaved via proteolytic
processing by caspase-1. The activation of caspase-1 is dependent on a
complex called the inflammasome, which is associated with cyto-
plasmic pattern recognition receptor signaling [26]. Another distinction
between IL-1α and IL-1β is in their ability to bind IL-R2; IL-R2 binds to
IL-1β with high affinity. However, IL-R2 is unable to initiate signaling
[27]. Major biological functions of IL-1β include the mediation of in-
flammation and the regulation of the immune response via the activa-
tion of Th1 and Th17 cells.
2.3. IL-1Ra
IL-1Ra, also designated as IL-1LF3, functions as a natural antagonist
for both IL-1α and IL-1β and is produced by monocytes and macro-
phages. All three cytokines share the same receptors, i.e., IL-1R1 and IL-
R2. Although IL-1Ra binds to specific receptors with almost the same
affinity as IL-1α and IL-1β, such binding does not initiate signal
transduction [17]. Accordingly, the function of IL-1Ra is to inhibit the
activity of IL-1α or IL-1β via competing with them for receptor binding
sites. The biological features of IL-1Ra have important medical appli-
cations; inhibition by IL-1Ra is utilized clinically to monitor treatment
responses of RA and type 2 diabetes mellitus [28,29]. In addition, there
is ongoing research to treat pancreatic cancer using IL-1Ra by targeting
IL-1α [30].
2.4. IL-33
IL-33 is a newly identified cytokine in the IL-1 subfamily and is
mainly expressed in normal endothelial stromal, epithelial and en-
dothelial cells. IL-33 acts as an alarm, such as when IL-1α is released
upon cell injury or tissue damage. Generally, IL-33 is converted into
mature bioactive forms by neutrophil elastase and cathepsin G and
calpain [31]. Mature IL-33 initiates its signaling pathway through the
formation of the IL-33/ST2L/IL1-RAcP complex, which is mainly ex-
pressed in Th2 cells. Mechanically, IL-33 mediates its immune response
primarily via polarized Th2 cells [32]. The signal transduction is similar
to that triggered by IL-1α. The IL-33/ST2L/IL1-RAcP complex also
causes the recruitment of MyD88 and further induces IRAK1/4, which
in turn activates TRAF6 and consequently drives the production of NF-
κB. As a result, IL-33 has been described as a nuclear factor with
transcriptional regulatory properties that interacts with the activation
of NF-κB as well as the P53 submit [33]. IL-33 is a “dual cytokine” that
exerts its regulatory and transcriptional effects by serving as a regular
Q. Tan et al. Cytokine and Growth Factor Reviews 44 (2018) 18–27

Table 1
Biological features of cytokines in the IL-1 subfamily and targeted agents.
IL-1 subfamily Family name Specific receptor Coreceptor Activity Targeted agents
(s)

IL-1α IL-1F1 IL-1RI；IL-1R2 IL-1RAcP Alarmin；Pro-inflammation； Th17 cell response；Nuclear Anakinra；Rilonacept；MABp1

transcription
IL-1β IL-1F2 IL-1RI；IL-1R2 IL-1RAcP Th17 cell response；Pro-inflammation； Anakinra；Rilonacept；Canakinumab
IL-1Ra IL-1F3 IL-1RI None Anti-inflammation None
IL-33 IL-1F4 ST2 IL-1RAcP Alarmin； Pro-inflammation； Th2 response；Nuclear transcription ANB020；CNTO7160

Fig. 1. Signaling pathways of the IL-1 subfamily and currently available inhibitors.

cytokine or a nuclear transcription factor.
The biological features of the IL-1 subfamily members are sum-
marized in Table 1, and their signaling pathways are described in Fig. 1.
(Table 2)
3. A review of glycolysis
Glycolysis is a determined sequence of enzyme-catalyzed reactions
that result in the conversion of glucose to lactate with the synthesis of
ATP. ATP plays an essential role in providing energy for most organ-
isms, especially under anaerobic conditions. In nearly all organisms,
glycolysis occurs in the cytosol of cells and can be divided into two
steps. The first step is the Embden–Meyerhof–Parnas pathway, whereby
glucose is converted to pyruvate, and the last step is the production of
lactate (Fig. 2) [10]. The flux through the glycolytic pathway is regu-
lated directly or indirectly by external signaling pathways and the en-
zymes of glycolysis. The Ras and PI3K signaling pathways are two
common pathways in the regulation of glycolysis. The former activates
MAPK and PI3K to trigger the transcription factor c-Myc, which directly
induces the expression of numerous glycolytic genes such as glucose
transporter (GLUT)1, hexokinase (HK)2, phosphofructokinase (PFK)
and enolase 1 (ENO1) as well as lactate dehydrogenase A (LDHA)
[34–37]. The latter pathway is activated by the ligand-bound receptor
tyrosine kinases (RTKs) through Akt and directly activates c-Myc
transcription factor and hypoxia inducible factor-1α (HIF-1α) to reg-
ulate GLUT1 and several glycolytic enzymes, including HK2, PFK, al-
dolase A (ALDOA) and LDHA [38–40]. The enzymes of this pathway
also play important roles in the regulation of glycolysis. The regulation
of glycolysis by the external signaling pathways and glycolytic enzymes
is summarized in Fig. 2.
4. The roles of the IL-1 subfamily in regulating glycolysis
As described above, glycolysis is the most important cellular energy
pathway, and its dysregulation is responsible for disease progression.
The IL-1 subfamily has been implicated in the regulation of glycolysis
by influencing glucose uptake or glycolytic enzyme activation.

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Q. Tan et al. Cytokine and Growth Factor Reviews 44 (2018) 18–27

Table 2
The potential roles of IL-1 subfamily members in glycolysis in disease.
Cytokine Disease model Cell type/Tissue Mechanism Effect on Reference
glycolysis

IL-1α RA Human rheumatoid synovial cell Fru(2,6)P2 ↑ ↑ [8]

IL-1α RA Human rheumatoid synovial cell Fru(2,6)P2↑, Glucose utilization ↑ ↑ [42]
IL-1α Severe sepsis HDF Glucose uptake ↑ ↑ [12]
IL-1α Glomerular Injury Murine mesangial cell HK2 ↑ ↑ [61]
IL-1α Hyperlactatemia Rat skeletal muscle cells Lactate ↑ ↑ [72]
IL-1α Severe scalding Rat skeletal muscle cells PFK ↑ ↑ [66]
IL-1α Fasted catheterized rat model Rat skeletal muscle Glucose uptake ↑ ↑ [49]
IL-1α / HDF from FAP of colon and normal state Glucose uptake ↑; Fru(2,6)P2 ↑ ↑ [11]
IL-1α / HuGi and PSF Glucose uptake ↑ ↑ [43]
IL-1α / Rat adipose cells No effect on glucose uptake None [53]
IL-1α / Porcine Sertoli cells LDHA expression ↑ ↑ [69]
IL-1α / Rat hepatocytes Lactate ↑ ↑ [71]
IL-1β Type 2 diabetes mellitus Rat pancreatic islets Glucokinase mRNA content ↓ ↓ [7]
IL-1β Type 2 diabetes mellitus HIT-T 15β-cells Glucokinase activity ↓ ↓ [65]
IL-1β Type 2 diabetes mellitus 3T3-L1 adipocytes GLUT4 translocation ↓； ↓ [60]
Glucose uptake ↓
IL-1β Type 2 diabetes mellitus Mouse pancreatic islets cells Glucokinase activity ↓ ↓ [59]
IL-1β RA Human rheumatoid synovial cell Fru(2,6)P2 ↑ ↑ [8]
IL-1β RA；osteoarthritis Human synovial cells from patient with osteoarthritis and Glucose uptake ↑ ↑ [41]
rheumatoid arthritis
IL-1β Osteoarthritis Rat articular chondrocytes GLUT1 mRNA ↑ ↑ [55]
IL-1β Osteoarthritis Human chondrocytes Glucose uptake ↑ ↑ [45]
IL-1β Glomerular Injury Murine mesangial cell HK2 ↑ ↑ [61]
IL-1β Allergic asthma Human airway epithelial cells; mouse tracheal epithelial LDHA ↑ ↑ [70]
cells
IL-1β Peritoneum injury Rat peritoneal mesothelial cells GLUT1 mRNA ↑ ↑ [54]
IL-1β Tendon injuries inTPCs from injured Achilles tendons from mouse HK2 mRNA ↑ ↑ [62]
IL-1β OSCC CAFs from patients with OSCC HK2 ↑ ↑ [9]
IL-1β Glioblastoma Glioblastoma cell lines HK2 mRNA ↑ ↑ [63]
IL-1β Hypoglycemia Spleen, lung, heart Glucose uptake ↑ ↑ [52]
IL-1β Rat model with intravenous Lung, spleen, liver, skin Glucose uptake ↑ ↑ [50,51]
injection
IL-1β / Rat ovarian cells Glucose uptake ↑ ↑ [47]
IL-1β / HuGi and PSF Glucose uptake ↑ ↑ [43]
IL-1β / Rat Sertoli cells Glucose transport ↑; LDHA ↑ ↑ [57]
IL-1β / Mouse astrocytes Glucose uptake ↑ ↑ [44]
IL-1β / Immature rat ovarian cells GLUT3 translocation ↑ ↑ [56]
IL-1β / Human peritoneal mesothelial cells Glucose uptake ↑ ↑ [46]
IL-1β / L6-GLUT4myc cells GLUT4 translocation ↑; Glucose ↑ [58]
uptake ↑
IL-1Ra GVHD Rat Th17 cells HK2 and GLUT1 ↓ ↓ [73]
IL-1Ra OSCC CAFs HK2 ↓ ↓ [9]
IL-1Ra Glomerular injury Murine mesangial cells HK2 ↓ ↓ [61]
IL-33 NSCLC NSCLC cells isolated from surgical tissues GLUT1 ↑; Glucose uptake ↑ ↑ [48]

4.1. The role of the IL-1 subfamily in the regulation of glycolysis through
targeting glucose uptake
Increasing evidence suggests that IL-1 subfamily members mediate
glycolysis by targeting glucose uptake into cells, which occurs during
the early stage of glycolysis. Findings from in vitro studies that are
consistent with this view include the following: [1] Both IL-1α and IL-
1β have been observed to stimulate glucose uptake in rheumatoid sy-
novial cells [41,42,2]. Bird et al. reported that IL-1α and IL-1β sig-
nificantly induced glucose uptake in human gingival fibroblasts (HuGi)
and porcine synoviocytes (PSF) by facilitating the maximal transport
velocity of the glucose transporter (Vmax) [43,3]. Administration of IL-
1α was found to be positively correlated with the improvement of
glucose uptake in the HDF of patients with FAP of the colon [11,4]. IL-
1β has been identified as a promoter of glucose uptake in different cell
types, including astrocytic brain cells [44], human chondrocytes [45],
human peritoneal mesothelial cells and rat ovarian cells [46,47,5]. IL-
33 enhances non-small cell lung cancer (NSCLC) cell outgrowth and
metastasis in vitro through upregulating membrane GLUT1 on NSCLC
cells via the IL-33/ST2 pathway, leading to enhanced glycolysis [48].
Furthermore, animal studies have confirmed the actions of the IL-1
subfamily in targeting glucose uptake. The main findings include the
following [1]: The intracerebroventricular injection of IL-1β in a rat
model increased glucose uptake in the lung, spleen, liver and skin,
whereas that of IL-1α enhanced glucose uptake in skeletal muscle,
diaphragm and heart [49–51,2]. Metzger et al performed an experiment
on mice bearing IL-1β-secreting tumors to investigate the chronic effect
of IL-1β on glucose uptake and discovered that IL-1β was associated
with increased glucose uptake through the peripheral tissues, including
the spleen, lung and heart [52]. These studies suggest a positive role of
the IL-1 subfamily in regulating glucose uptake.
Several studies of the associations between the IL-1 subfamily and
glucose uptake have been conducted in recent years. Further studies are
needed to address the following issues: [1] One study found that IL-1α
did not trigger a change in glucose uptake in rat adipose cells, sug-
gesting that cell sensitivity to IL-1 subfamily members may vary among
different cell types [53,2]. IL-1β has been found to have positive and
negative roles on glucose uptake, which seem to be associated with cell
type. In addition, IL-1β was found to enhance glucose uptake in rat
peritoneal mesothelial cells and rat articular chondrocytes by in-
creasing GLUT1 mRNA [54,55]. In immature rat ovarian cells, in-
creased glucose uptake was induced by IL-1β via GLUT3 production
[56]. Riera et al confirmed that IL-1β activates the PI3K/PKB pathway
to upregulate glucose transport in Sertoli cells [57]. In a line of skeletal
muscle cells (L6-GLUT4myc cells), IL-1β facilitated glucose uptake by
increasing GLUT4 translocation via the activation of AMPK [58].

21
Q. Tan et al.
Fig. 2. The Ras pathway and the PI3K-AKT-mTOR pathway in the regulation of glycolysis.
Nevertheless, IL-1β acts as a strong inhibitor of glucose uptake in some
tissues, such as liver and pancreatic islets, via the downregulation of
GLUT2 expression [52,59]. Interestingly, a report revealed that IL-1β
inhibited insulin-induced glucose uptake via decreasing GLUT4 trans-
location in 3T3-L1 adipocytes, which conflicts with the findings in
skeletal muscle cells (described above) [60]. These data suggest that IL-
1β may have different roles in glucose uptake depending on cell type.
Further studies are needed to identify the mechanisms underlying IL-
1β's effects on glucose uptake.
4.2. The role of the IL-1 subfamily in the regulation of glycolysis via
glycolytic enzyme activation
IL-1 subfamily cytokines have been found to influence the activities
of glycolytic enzymes, including HK, Glucokinase, PFK and LDHA, and
thereby lead to glycolysis changes.
4.2.1. The IL-1 subfamily and HK activity
HK catalyzes the conversion of glucose to G-6-P when glucose enters
the cell. In vitro studies have been conducted to verify the role of IL-1α
or IL-1β in HK activity. Taneja et al. reported that IL-1α and IL-1β are
two common and important activators of HK activity and that both
cytokines increase HK activity through the IL-1 receptor-, Ras- and
classic MAPK pathways [61]. In vitro experiments with injured tendon-
derived progenitor cells from mouse Achilles tendons revealed a cor-
relation between IL-1β overexpression and the expression of HK2 [62].
In another study, IL-1β enhanced HK2 expression and appeared to act
as a transcription factor that induces chromatin reorganization at the
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Cytokine and Growth Factor Reviews 44 (2018) 18–27
HK2 promoter [63]. Recently, increased IL-1β derived from oral squa-
mous cell carcinoma (OSCC) in the tumor microenvironment (TME) and
a correlation between IL-1β secretion and the glycolysis of cancer-as-
sociated fibroblasts (CAFs) in vitro was described by Wu et al [9]. These
results suggest that IL-1β secreted by OSCC cells increases HK2 ex-
pression in CAFs. As a result, the lactate produced by CAFs serves as
'fuel' for the proliferation of cancer cells. However, IL-1β appears to be a
functional mediator between CAFs and cancer cells. Interestingly,
macrophages are the primary manufacturers of IL-1β, and one hallmark
of cancer is aerobic glycolysis (the Warburg effect) [64]. Thus, it re-
mains to be determined whether tumor-associated macrophages (TAM),
which are considered to be central players in the TME, can enhance the
glycolysis of cancer cells through the production of IL-1β or IL-1β by
cancer cells, which would increase the activity and positive role of
TAM. This area is a major topic of interest to our research group. The
regulatory associations between TAM and cancer cells require further
study.
4.2.2. The role of the IL-1 subfamily in glucokinase activity
Glucokinase is another enzyme that catalyzes the conversion of
glucose to G-6-P; however, it specific to hepatocytes and β cells. Studies
of pancreatic islets and HIT-T15 β-cells have shown that IL-1β is a
strong inhibitor of glucokinase expression. The inhibition of glucoki-
nase reduces glycolysis, leading to decreased insulin release, which is
considered a pathogenic factor of type 2 diabetes mellitus [7,59,65]. To
investigate the role of IL-1β in regulating glucokinase activity, in-
vestigators measured islet glucokinase mRNA through polymerase
chain reaction (PCR) and the concentration of nitric oxide (NO), which
Q. Tan et al.
is a positive regulator in the dysfunction of pancreatic β-cells. They
found that IL-1β provoked a delayed increase in the production of NO
but reduced the islet content of glucokinase mRNA. This effects were
attenuated due to the activity of N-monomethyl-L-arginine (NMA), an
inhibitor of NO synthase, suggesting that IL-1β induces a decrease in
the synthesis of islet glucokinase protein by an NO-dependent me-
chanism [7]. The different roles of IL-1β in the conversion of glucose to
G-6-P depend on the cell type involved.
4.2.3. The IL-1 subfamily affects PFK activity
In catalyzing the rate-limiting step of the conversion of fructose-6-
phosphate (F6P) to fructose-1,6-bisphosphate (F1,6P2), PFK functions
as a strong regulator of flux through glycolysis. An experimental mouse
model of severe scalding revealed that IL-1α can enhance PFK activity
in skeletal muscles and lower pyruvate dehydrogenase (PDH) activity,
which is associated with glucose oxidation [66]. In addition, PFK can be
stimulated by Fru(2,6)P2. Accordingly, an increase in Fru(2,6)P2 has
been proposed to be part of the mechanism by which IL-1α induces PFK
in rheumatoid synovial cells [8,42,67]. Taylor used HDF from a normal
colon and FAP of the colon and confirmed that Fru(2,6)P2 was actively
regulated by IL-1α(11). These findings suggest that the role of IL-1α in
the regulation of glycolysis involves both direct and indirect targeting
of PFK.
4.2.4. The IL-1 subfamily plays an active role in LDHA expression
Lactate is the end product of glycolysis, and its accumulation is
among the most sensitive parameters for detecting improvements in
glycolysis. LDHA is a rate-limiting enzyme in glycolysis and has es-
sential roles in the conversion of pyruvate to lactate [68]. Correlations
between IL-1 subfamily members and LDHA have also been demon-
strated in vitro studies. Researchers have revealed that IL-1α stimulates
lactate production in porcine Sertoli cells by upregulating LDHA ex-
pression [69]. In vitro and animal studies using an allergic asthma
model to investigate the expression of LDHA induced by IL-1α or IL-1β
revealed active roles of these cytokines in the regulation of LDHA in
human airway epithelial cells and mouse tracheal epithelial cells [70].
Riera et al. investigated the mechanism of IL-1β-triggered glycolysis
increase by utilizing Sertoli cells and found that IL-1β enhanced LDHA
mRNA levels via the ERK1/2 pathway [57].
Collectively, the above-described studies reveal that IL-1α, IL-1β
and IL-33 influence glycolysis via different mechanisms. Additional
studies have found correlations between IL-1 subfamily members and
glycolysis for which the underlying mechanisms remain unknown: [1]
Vaartjes et al. reported that IL-1α increased lactate accumulation in rat
hepatocytes in vitro and depressed glycogen synthesis [71,2]. Admin-
istration of IL-1β induced hyperlactatemia in a rat model and enhanced
lactate content in rat skeletal muscle while decreasing the activity of
PDH [72]. These studies suggest that cytokines in the IL-1 subfamily
have important roles in glycolysis not only in targeting glucose uptake
or glycolytic enzyme activation but also in influencing alternative
pathways of glucose metabolism. This possibility requires further in-
vestigation. The mechanisms by which these cytokines influence gly-
colysis are varied and seem to be dependent on cell type. Regardless,
the abovementioned studies support to the view that IL-1 subfamily
cytokines and the process of glycolysis are correlated.
4.2.5. The potential role of IL-1Ra as antagonist in glycolysis regulation
As one of the main members of the IL-1 subfamily and the natural
antagonist of both IL-1α and IL-1β, IL-1Ra dampens IL-1α- or IL-1β-
enhanced glycolysis via competing with these cytokines for receptor
binding sites. Consistent with this observation, a study demonstrated
that IL-1Ra could prevent IL-1α or IL-1β stimulation of HK activity
[61]. In a study of Graf-versus-host disease (GVHD), Th17 cells were
found to be the central players in GVHD, and IL-1β was found to be
involved in the development of Th17 cells through inducing the ex-
pression of glycolysis-related genes, such as HK2 and GLUT1. However,
23
Cytokine and Growth Factor Reviews 44 (2018) 18–27
IL-1Ra significantly suppressed the IL-1β-induced effects on the ex-
pression of glycolysis-related genes in Th17 cells, slowing the progress
of the disease [73]. Furthermore, IL-1Ra was found to decrease the
development of CAFs, the central players in TME (described above), in
samples of patients with OSCC.
However, IL-1β plays a key role in TME and induces the develop-
ment of CAFs. This latter effect was neutralized by IL-1Ra in a previous
study, suggesting that IL-1α and IL-1β have key functions in the pro-
gression of disease and that IL-1α, IL-1β and IL-1Ra may also play roles
in the targeted agent [9].
5. The dysregulation of glycolysis caused by the IL-1 subfamily in
disease
As described in the previous section, IL-1 subfamily-induced effects
on glycolysis have been linked to the dysregulation of glycolysis, which
contributes to the development and progression of several glycolysis-
related diseases. Evidence that the dysregulation of glycolysis was in-
duced by the IL-1 subfamily in disease is described below.
5.1. Type 2 diabetes
Type 2 diabetes is characterized by diminished insulin secretion and
insulin resistance, which result from decreased glycolysis in islet β-cells
and insulin-sensitive tissues such as adipose tissue. IL-1β has been im-
plicated in the occurrence and development of type 2 diabetes in as-
sociation with the downregulation of glucokinase expression in β-cells
and decreased glucose uptake in adipocytes, as described above. These
observations suggest the potential of the inhibition of IL-1β activity as a
new targeted therapeutic strategy in type 2 diabetes patients
[7,59,60,65]. In a randomized, placebo-controlled, double-blind Phase
I/II clinical trial, patients with type 2 diabetes received a novel vaccine
against IL-1β and showed improved glycemia as a result. Furthermore,
the vaccine was suggested to be safe for use in clinical practice [74].
5.2. Rheumatoid arthritis
Increased glycolysis is associated with increased accumulation of
lactate in joints. This accumulation inhibits the synthesis of matrix
macromolecules, such as proteoglycans, in synovial cells, leading to
joint degeneration; this process has been described as a mechanism of
RA. Several lines of evidence described above suggest that both IL-1α
and IL-1β play active roles in glycolysis and its inhibition in synovial
cells. IL-1 blockers such as anakinra, which is a recombinant human IL-
1 receptor antagonist (IL-1Ra, described below) and has been FDA-
approved for RA, offer potential strategies for treatment [8,41,42,67].
Another study involving synovium and fibroblast-like synoviocytes
from patients with RA demonstrated the efficacy of 2-deoxy-D-glucose
(2-DG), a glycolysis inhibitor, in the treatment of RA [75]. Collectively,
these findings suggest that the increased glycolysis in synovial cells
caused by IL-1α and IL-1β plays a pivotal role in the pathogenesis of
RA.
5.3. Cancer
Cancer cells use glycolysis as the main pathway for obtaining en-
ergy. Even under a sufficient O2 supply, the tumor cells seem to prefer
to rely on glycolysis for the production of ATP as fuel. Therefore, sig-
nificant metabolic characteristics of cancer tissue have been found to be
associated with high glycolysis rates [15]. Recent research has revealed
that lactate, a product of the glycolysis pathway, is the most important
energy resource for cancer cells. These findings suggest that high
aerobic glycolysis is a feature of cancer cells and can be used as a target
in cancer therapy [76]. IL-1β and IL-33 were described as common
promoters in the regulation of glycolysis in studies of OSCC and NSCLC
[9,48]. These observations support the concept that an IL-1 subfamily
Q. Tan et al.
blockade as a potential therapeutic target may be beneficial for cancer
patients. Regarding NSCLC, a current phase III trial is seeking patients
to evaluate the safety and efficacy of Canakinumab (a neutralizing
monoclonal anti-IL-1β antibody; described below) (ClinicalTrials.gov
Identifier: NCT03447769).
5.4. Other glycolysis-related diseases
Correlations of the IL-1 subfamily with glycolysis dysfunction have
been reported for some glycolysis-related diseases, including osteoar-
thritis and asthma, in a limited number of studies, However, more at-
tention should be paid to the possibility that the IL-1 subfamily has
important roles in the pathogenesis of theses disease for the following
reasons: [1] Lactate inhibits the synthesis of matrix macromolecules in
chondrocytes and is believed to be a mechanism of osteoarthritis
[41,2]. Increases in lactate in human nasal epithelial cells from asth-
matics relative to those from healthy subjects have been observed,
suggesting the importance of dysregulated glycolysis in allergies [41].
Studies (described above) have demonstrated that IL-1β, as a positive
regulator, is important in augmenting glycolysis in human chon-
drocytes and human nasal epithelial cells. Currently, a phase I/II trial in
patients with asthma is underway to determine the effect of anakinra on
asthma (ClinicalTrials.gov Identifier: NCT03513458).
6. Therapies available to inhibit the actions of the IL-1 subfamily
As described above, studies have identified correlations between the
IL-1 subfamily and the dysregulation of glycolysis, which seem to play
an important role in the pathogenesis of disease. The use of IL-Ra has
been shown to partially correct glycolysis dysfunction due to its an-
tagonistic effects. On the other hand, IL-1 subfamily blockers may re-
present promising adjuvant therapies. Here, we summarize current
targeted agents that antagonize the actions of these cytokines (see
Fig. 2). Currently, therapeutic strategies include the following: [1]
anakinra, the recombinant form of hIL-1Ra [2]; soluble decoy receptors,
including rilonacept; and [3] neutralizing monoclonal anti-IL-1β anti-
bodies, such as canakinumab. Anakinra, rilonacept and canakinumab
have been widely studied and FDA-approved for inflammatory diseases
such as gout and type 2 diabetes. Their effects on inflammatory diseases
and the associated mechanisms are reviewed in previous work [77]. In
addition, a monoclonal antibody directed against IL-1α (MABp1) and
the monoclonal anti-IL-33R antibody (CNTO7160) as well as a neu-
tralizing anti-IL-33 (ANB020) are being investigated in clinical trials.
MABp1, a neutralizing monoclonal anti-IL-1α antibody, appears to
be effective in inhibiting the progression of type 2 diabetes mellitus and
has been found to be effective in the treatment of moderate to severe
hidradenitis suppurativa [78,79]. Furthermore, in a phase III trial of
patients with metastatic colorectal cancer, MABp1 treatment led to
improvements in the prognosis of patients ineligible for standard che-
motherapy, including the relief of cancer-associated symptoms [80].
MABp1 has been shown to have a satisfactory safety profile. These
observations indicate that MABp1 may be another promising agent for
targeting IL-1α; further studies are needed to confirm this possibility
and develop clinical applications. Currently, the efficacy of MABp1 in
treating patients with atopic dermatitis is being tested in a phase II
study (ClinicalTrials.gov Identifier: NCT03496974).
CNTO-7160, a monoclonal antibody to IL-33R, inhibits IL-33 by
preventing it from binding to its receptor (ST2) and was designed to
treat patients with severe asthma. Presently, this antibody is in a phase I
clinical trial (ClinicalTrials.gov Identifier: NCT02345928). No data
have yet been reported.
ANB020 is another potent IL-33-targeted agent that directly neu-
tralizes IL-33. It has been licensed and has passed a phase II clinical trial
for the treatment of moderate-to-severe atopic dermatitis. Data are
available from AnaptysBio reports (AnaptysBio Reports Positive
Topline Proof-of-Concept Data from Phase 2a Clinical Trial of ANB020
24
Cytokine and Growth Factor Reviews 44 (2018) 18–27
in Atopic Dermatitis) and represent the first proof-of-concept data re-
garding anti-IL-33 activity. Research to confirm and expand its clinical
applications is in progress. For example, a phase II clinical trial is un-
derway to assess the safety and efficacy of ANB020 in adult patients
with severe eosinophilic asthma (ClinicalTrials.gov Identifier:
NCT03469934).
The findings described above showed that these targeted agents
have been widely acknowledged and have applications in clinical
practice. The targeted agents are summarized in Table 1.
7. Conclusions and future directions
In summary, the cytokines of the IL-1 subfamily act as promoters in
regulating glycolysis. However, some reports have revealed negative
roles of these cytokines in glycolysis in disease. The specific roles of
these cytokines in regulating glycolysis might depend on cell type and
the type of cytokine.
The correlations between the IL-1 subfamily and the dysfunction of
glycolysis in disease states should not be neglected. Our review pro-
vides the first summary of the potential roles of IL-1 subfamily members
in glycolysis in disease. Previous studies have focused mainly the re-
lationships between inflammatory tissue injury induced by these cyto-
kines and the pathogenesis of disease. However, IL-1 subfamily-induced
changes in glycolysis in disease states are gradually being identified and
becoming recognized. Given the findings summarized in the present
review, it is essential that the following aspects be addressed in future
studies: [1] It is clear that inflammatory factors, such as the cytokines of
IL-1 subfamily, can influence glycolysis. Positron emission tomography
(PET) detects the high aerobic glycolysis of malignant tumors [81],
with standardized uptake (SUVmax) measured by PET serving as an
index of metabolism and reflecting the rate of glycolysis in tissues.
Therefore, whether SUVmax is positively correlated with IL-1α, IL-1β
and IL-33 in peripheral blood warrants investigation [2]. Patients suf-
fering from glycolysis-related diseases such as type 2 diabetes or RA
have been shown to benefit from anti-IL-1 agents [77]. Since aerobic
glycolysis is the main pathway by which cancer cells obtain energy,
whether IL-1 subfamily blockers can improve prognosis in cancer pa-
tients, e.g., by prolonging survival time and relieving cancer-associated
symptoms such as anorexia, fatigue and pain, should be investigated.
The blocking of the IL-1 subfamily has been performed in clinical trials
of cancer treatment and has been reported effective for patients with
advanced colorectal cancer [80]. However, few studies have evaluated
whether IL-1 subfamily blockers improve prognosis in lung-cancer pa-
tients, which is a future research direction of our group. Furthermore,
inflammatory factors, especially the cytokines of the IL-1 subfamily, in
TME warrant investigation and will be a focus of our future studies.
Conflict of interests
The authors declare that they have no competing interests.
Acknowledgements
This work was greatly supported by the National Natural Science
Foundation of China (Nos. 81572942 and No. 81770096), and the
Hubei province natural science foundation of China (No. 2017CFB260).
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Yan ling Ma received a master's degree from the Union
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metastatic castration-resistant prostate cancer, JAMA Oncol. (2017) e173588.

Qi Tan started his postgraduate work at the Department of
Respiratory, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology in
2017.His research interests in the role and mechanism of
action of inflammatory cytokines in cancer metabolism.
Ping Luo obtained her PhD title in the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences in 2017,
working at the Center for Translational Medicine, Union
Hospital, Tongji Medical College, Huazhong University of
Science and Technology since 2017. Her work mainly fo-
cuses on the methods development of liquid chromato-
graphy-mass spectrometry-based metabolomics and appli-
cations in diseases study. Main clinical and research interest
includes investigation of metabolic disorders in different
diseases and discovery of novel biomarkers for diseases
diagnosis and prognosis through application of transla-
tional medicine technology.

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Q. Tan et al. Cytokine and Growth Factor Reviews 44 (2018) 18–27

Guan zhou Ma started MD studies at Union Hospital,
Tongji Medical College, Huazhong University of Science
and Technology in 2018. His research is centered on the
potential relationship between a series of environmental
exposures and respiratory disease.
Professor Yang Jin obtained his PhD in Union Hospital,
Tongji Medical College, Huazhong University of Science
and Technology in 2003.He is a doctor of the Department of
Respiratory, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology.His re-
search focuses on cancer metabolism and the role of gly-
colysis in lung cancer cells.He is head of scientific research
office in Union Hospital, He is also a member of the Chinese
Thoracic Society.

PeiYuan Mei started his postgraduate work at Department

of Cardiothoracic Surgery, Union Hospital, Tongji Medical
College, Huazhong University of Science and Technology in
2017. His research focuses on the relationship between in-
flammatory cytokines from IL-1 family and glucose meta-
bolism of lung cancer cells.

27