Advances in Bioscience and Biotechnology, 2013, 4, 860-865 ABB
http://dx.doi.org/10.4236/abb.2013.49114 Published Online September 2013 (http://www.scirp.org/journal/abb/)
Cytokine release in sepsis
Ian Burkovskiy1*, Joel Sardinha1*, Juan Zhou2,3, Christian Lehmann1,2,3#
1Department of Pharmacology, Dalhousie University, Halifax, Canada
2Department of Anesthesia, Dalhousie University, Halifax, Canada
3Department of Microbiology & Immunology, Dalhousie University, Halifax, Canada
Received 1 June 2013; revised 1 July 2013; accepted 1 August 2013
Copyright © 2013 Ian Burkovskiy et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Despite the advances in the therapeutic approaches,
health care protocols and policies, sepsis continues to
be an important problem in clinical medicine. High
lethality of sepsis cases calls for a detailed and criti-
cally important study of the pathophysiology of sepsis.
In this review, we discuss pathomechanisms of sepsis
and the role of cytokines that are released in sepsis.
We propose that the systemic levels of cytokines are
not always reflecting the pathological picture and the
immune status of the patient. One of the emerging
approaches which may bring an effective treatment
strategy exploits the endocannabinoid system for its
immunomodulatory properties. Following from that,
the research in this particular field is very important
as it can bring understanding behind the complicated
pathophysiology of sepsis.
Keywords: Sepsis; Cytokine; Inflammation;
Immunology
1. INTRODUCTION
Sepsis is the systemic inflammatory resp onse to an infec-
tion that is usually associated with tissue hypoperfusion
and multi-organ dysfunction [1]. According to generally
accepted definitions, there are three clinical stages of
sepsis-sepsis, severe sepsis and septic shock. Each indi-
vidual stage is based on the complexity and the severity
of the symptoms. Prevalence of septic shock and severe
sepsis in intensive care units and emergency rooms con-
tinues to be high, despite the advances in surgical critical
care and techniques, therapeutic approaches, establish-
ment of new health care protocols and policies and de-
velopment of new drugs [2,3]. One of the fundamental
pathological characteristics of sepsis is the inability to
maintain the balance between excessive and inadequate
inflammation [4].
Sepsis is considered to be the 10th leading cause of
death in the United States, with approximately a million
severe sepsis cases each year in the United States and an
estimated 18 million cases of sepsis globally [5,6]. Mod-
ern therapeutic approach es are more frequent in utilizin g
aggressive immunosuppressive and chemotherapeutic
treatments that compromise normal defense mechanisms
and contribute to the increase in sepsis case numbers [2].
In addition to being a critical health condition, severe
sepsis also puts a heavy socio-economic strain on the
health care system [7]. Literature reports that the care of
patients with sepsis brings an annual cost of the care to
$17 billion, in the United States alone [5]. In Canada, a
study conducted by Letarte et al. [7] investigated the
costs of severe sepsis and septic shock in the province of
Quebec. The study reported a cost estimate between $36.4
and $72.9 millio n per year and co ncluded that the co st of
severe sepsis is a significant economical burden for the
Quebec health care system [7]. Finally, the patients that
survive severe sepsis have a substantial reduction in their
overall quality of life [8,9].
2. ETIOLOGY AND
PATHOMECHANISMS OF SEPSIS
Etiologically, any infectious agent that enters the blood-
stream of a patient and generates a systemic immune
response can cause sepsis. However, the presence of the
pathogen in the blood is not a requirement for th e clinical
symptoms of sepsis to manifest themselves—as the pres-
ence of pathogen’s signaling molecules or inflammatory
mediators, which are released into the circulation from
the source of infection, is sufficient for sepsis induction
[10]. While sepsis can potentially be caused by many
infectious agents such as bacteria, fungi, parasites or vi rus
[11], the majority of cases of sepsis are reported to be
due to bact er i a [10].
*These authors contributed equally.
#Corresponding author.

I. Burkovskiy et al. / Advances in Bio science and Biotechnology 4 (2013) 860-865 861
The detection of the bacteria that causes sepsis st ron gly
depends on the severity of the clinical picture with bacte-
ria being detected in approximately 20% to 40% of pa-
tients with severe sepsis and in 40% to 70% of cases with
septic shock [12]. One European study reported that the
most frequent infectious agent that was associated with
sepsis was Escherichia coli, with 22.7% share of de-
tected cases [13]. A more detailed study by Vincent et al.
[14] surveyed the prevalence and outcomes of infection
in intensive care units from 75 countries. The results
revealed that the microbiological culture results were
positive in 70% of the infected patients with 62% of the
positive isolates being gram-negative organisms, 47% be-
ing gram-positive, and 19% being fungal in [14].
The first step in host defense is the recognition of mi-
croorganisms via binding of pattern-recognition recap-
tors, such as the Toll-like receptor family (TLRs) to highly
conserved molecules called pathogen-associated molecu-
lar proteins (PAMPs) [15]. TLRs then recruit adaptor
proteins to the cell surface and the adaptor proteins, in
turn, activate a series of cytoplasmic kinases, initiating
cascades that activate various transcription factors [15].
Genes that are induced by these transcription factors pre-
pare the cell to undergo one of the potential main re-
sponses—rapidly undergoing apoptosis if the cell is over-
whelmingly infected, fighting the infection with pro-in-
flammatory molecules and proliferating or suppressing
the inflammatory reaction if no pathogens are longer de-
tected [15].
First responding cells are monocytes and macrophages,
which through induction of early response genes such as
TNFα and IL-6 rapidly produce inflammatory cytokines
and chemokines, amplifying the inflammatory response
[15]. This is followed by an activation of lymphocytes as
an adaptive immune response, as well as the coordination
of later phases of the immune response [15]. Addition-
ally, nitric oxide (NO) that is produced by endothelial
cells induces vasodilation and an increase in leukocyte
delivery to the sites of immune-activity [15].
3. ENDOCANNABINOID SYSTEM
The endocannabionoid system has emerged as a potential
therapeutic target in sepsis treatment due to its immune
modulatory functions. This endogenous system derives
its name from the plant Cannabis sativa which contains
many phytocannabinoids that activate endocannabinoid
receptors within our bodies. The two most well charac-
terized endocannabinoid receptors are cannabinoid recap-
tor 1 (CB1) and cannabinoid receptor 2 (CB2). The CB1
receptors are found throughout our bodies, but are highly
concentrated in our central nervous system where they
are implicated in modulating neurotransmitter release.
Alternatively, the CB2 receptors are mainly localized on
the surface of our immune cells, thus implicating a role
within our immune sy stem. Exploiting the activi ty of these
receptors may prove to be beneficial in sepsis treatment.
It has been well established that activation of the CB2
receptors initiates immunosuppressive mechanisms. One
component of this suppressive mechanism involves al-
tering the cytokines released by immune cells. CB2 re-
ceptor activation results in a reduction of pro-inflamma-
tory cytokine release from leukocytes as well as an in-
creased secretion of immunosuppressive cytokines. This
outcome may hav e a beneficial effect if initiated during a
pro-inflammatory phase of the septic cascade. However,
due to the variability of the immune state during septic
progression, immunosuppressive therapeutics can be det-
rimental, leaving the patient vulnerable to infections. As
a result, measurement of cytokine levels in the blood was
suggested as a method for detecting the condition of the
patient’s immune system. A proper understanding of the
patient’s immune state during sepsis is vital for appropri-
ate treatments.
4. CYTOKINE RELEASE
Cytokines are low molecular weight signaling molecules
secreted by a variety of cells that are used for cellular
communication. Cytokines exist as proteins, glycopro-
teins, or peptides, and have functional roles in immuno-
modulation as well as development. They are involved in
cellular activation, trafficking, signaling events, prolif-
eration, differentiation and migration [16]. Cy t oki nes exert
their effects on targets by binding to cell surface recap-
tors. Receptor activation subsequently leads to modula-
tion of intracellular cascades, eventually causing a bio-
logical effect. A few cytokines are constit utively expresses,
however a majority of cytokines is produced in response
to antigens, other cytokines, or cellular stressors. Due to
the facultative expression of these molecules, gene ex-
pression of cytokines is tightly regulated, with rapid tran-
scription and translation of proteins on demand. As an
example, activation of transcription factor nuclear factor
κB (NF-κB) causes the rapid production and release of
pro-inflammatory cytokines such as IL-1 [16].
Cytokines exert their effects in a dose dependent man-
ner and have relatively short half lives in the extracellu-
lar environment. Therefore, cytokine levels can fluctuate
drastically in microenv ironments during their short dura-
tion of action. Once cytokines are released, they can act
on their targets in either an autocrine or paracrine fashion.
Multiple cytokines can also interact in the extracellular
environment, causing a plethora of different effects. All
cytokines are pleiotropic, which indicates that they can
have variable effects based on the receptors they bind to.
Alternatively, many cytokines can be redundant because
they can have the same functional outcome. Different

I. Burkovskiy et al. / Advances in Bio science and Biotechnology 4 (2013) 860-865 862
cytokines can act in a synergistic manner, which would
elevate the response to a level greater than the additive
effects of the individual cytokines. In contrast, cytokines
can also behave antagonistically, where the effects of
some cytokines may be diminished by others. This flexi-
bility, of multiple functional outcomes, equips the im-
mune system to activate and coordinate entire networks
of immune cells from a small number of cytokine pro-
ducing cell types [17].
Cytokines can be categorized based on their functional
response into Type I or T-helper I (Th1) and Type II or
T-helper 2 (Th2). Th1 cytokines are responsible for in-
fections that produce a cell mediated immune response,
while Th2 cytokines produce an antibody mediated im-
mune response [17]. Another method of categorizing
cytokines is based on their immune elicited outcome into
either pro-inflammatory or anti-inflammatory cytokines
(Table 1). Pro-inflammatory cytokines help up regulate
the immune system when antigens are detected, or during
cellular stressors. Anti-inflammatory cytokines help abate
and modulate an up-regulated immune response bringing
it back to homeostasis after the threat has been elimi-
nated. The major pro-inflammatory cytokines discussed
in this paper are TNFα, IL-1β, IL-6 and IL-17, while the
main anti-inflammatory cytokines discussed will be IL-10,
IL-4, IL-13 and TGF-β (Table 1).
5. PRO-INFLAMMATORY CYTOKINES
Tumour necrosis factor alpha (TNFα) is a pro-inflam-
matory cytokine with a primary function to promote in-
flammation. This cytokine achieves this by signaling
through specific receptors to induce gene expression of
key inflammatory products. TNFα is shown to be a po-
tent inducer of endothelial adhesion molecules to enable
continuous recruitment of immune cells to help fight the
infection [18]. TNF-α and IL-1 have also been demon-
strated to act synergistically in order to initiate and pro-
mote inflammatory signalling pathways [19].
Interleukin-6 (IL-6) is classified as both a pro-in-
flammatory and anti-inflammatory cytok ine and is linked
with bacterial sepsis. Serum levels of IL-6 have been
regarded as a surrogate marker for disease severity in
sepsis. Moreover, IL-6 has also been shown to be an im-
portant mediator of fever and immuno-acute phase re-
sponses [18]. This particular cytokine was also exten-
sively investigated in the past few years due to its in-
volvement in differentiating the newly defined T helper
17 (TH17) subset of CD4 + T cells, among with TGF-β
and IL-21 [18]. In addition, IL-6 appears to b e crucial to
the production of functional tissue factor complexes [20].
Interleukin-1 beta (IL-1β) is a pro-inflammatory cyto-
kine that is a potent inducer of endothelial adhesion
molecules to enable further recruitment of immune cells,
Table 1. Anti-inflammatory/inflammtory cytokines and their functional role in sepsis.
Inflammatory
cytokines Function in sepsis
TNFα Promotion of inflammation, potent inducer of endothelial adhesion molecules. May act synergistically with IL-1 to promote
and initiate inflammatory pathways.
IL-1β
Potent inducer of endothelial adhesion molecules to enable recruitment of immune cells. Involved in promotion of
inflammatory signaling pathway, IL-1β can also activate the release of NO by both the endothelial and vascular smooth
muscle cells.
IL-6 Important mediator of fever and immno-acute phase responses, involved in differentiating newly defined T helper 17 (TH17)
subset of CD4 + T cells. Also involved in production of functional tissue factor complexes.
IL-17/IL-17A Involved in recruitment of monocytes and neutrophils to inflammation site, also expressed in natural killer (NK) cells. May have indirect chemo-attractive properties due to the upregulation of granulocyte colony stimulaing factor (G-CSF) and CXC
chemokines.
Anti-inflammatory
cytokines
TGF-β Modulates the activity of other cytokines through either enhancing or antagonizing effects. Can diminish the proliferation
and differentiation of T cells and B cells. Can also promote a state of resolution and repair.
IL-4 Not released systemically into the bloostream during sepsis. IL-4 suppresses macrophage activity and has gen eral
immunosuppressive effects.
IL-10 Involved in modulation of the pro-inflammatory response, ser ves to move the immune system from a cell mediated response
to a humoral response. Blocks the innate immune response. Can also indirectly block pro-inflammatory cytokine activity.
IL-13 Affects cell surface expression of different receptors in macrophages and monocytes. Down regulates CD-14 receptor
expression, also down regulates the expression of many pro-inflammatory cytokines such as TNFα & IL-1 in monocytes.

I. Burkovskiy et al. / Advances in Bio science and Biotechnology 4 (2013) 860-865 863
involved in promotion of inflammatory signaling path-
ways [18]. IL-1β can also activate the release of NO by
both the endothelial and vascular smooth muscle cells,
via increased transcription and activity of the inducible
form of NO synthase [18].
Interleukin-17 or Interleukin-17A (IL-17/IL-17A) is a
pro-inflammatory cytokine that is produced by T helper
17, a subset of CD4 + T cells. IL-17 is involved in re-
cruitment of monocytes and neutrophils to inflammation
site [18]. IL-17 is also expressed in natural killer (NK)
cells and this pro-inflammato ry cytokin e has been shown
to be detrimental in the survival outcome of common
lymphoid progenitor (CLP), the murine model of po-
lymicrobial sepsis [21]. Literature reports that IL-17A
may also be considered to have indirect chemoattractive
properties due to the up-regulation of granulocyte col-
ony-stimulating factor (G-CSF) and CXC chemokines,
resulting in enhanced recruitment of neutrophils to the
site of infection, resulting in an efficient bacterial clear-
ance [22].
6. ANTI-INFLAMMATORY CYTOKINES
One of the main anti-inflammatory cytokines is IL-10.
IL-10 helps modulate the pro-inflammatory response
during early stages of sepsis by limiting exaggerated pro-
inflammatory effects as well as making targets more tol-
erant to repeated pro-inflammatory stimuli [15]. How-
ever, in later stages, more sustained levels of IL-10 serve
to move the immune system from a cell mediated re-
sponse (Th1; innate immunity) to a humoral response
(Th2; adaptive immunity). Known cellular sources of
IL-10 include macrophages, dendritic cells, B-lympho-
cytes, T-regulatory cells (TREGS), and natural killer T
cells (NKT cells) [23]. IL-10 blocks the innate immune
response by inhibiting development and cytokine release
by Th1 cells, as well as blocking production of certain
pro-inflammatory cytokines. Apart from blocking pro-
inflammatory cytokine release, IL-10 can also indirectly
block pro-inflammatory cytokine activity by inducing the
expression of soluble antagonistic receptors such as IL-1
receptor antagonist (IL-1RA) and soluble TNF receptors
(sTNFR). These soluble antagonistic receptors bind to
the pro-inflammatory cytokines and prevent them from
activating their targets, effectively diminishing the extent
of pro-inflammatory stimulation. The role of IL-10 in
sepsis pathogenesis is not well understood. Conflicting
results have been shown by different groups using IL-10
in survival outcome studies [24]. One study pretreated
mice with anti-IL-10 antibody before inducing a septic
state and found a decreased ability to survive in com-
parison to controls [25]. Conversely, another study tested
mice lacking the IL-10 gene and observed survival wh en
anti-IL-10 antibodies were administered at different time
points [26]. These IL-10 deficient mice showed impro ved
survival only if anti-IL-10 antibodies were given after a
delay of initiating the septic challenge, presumably fol-
lowing the initial pro-inflammatory cascade, but not when
anti-IL-10 antibodies were administered directly after the
septic challenge. The results of these, as well as many
other studies, indicate that the role of IL-10 in sepsis may
be dependent of immune state of the patient, and effec-
tive treatments involving this cytokine are time critical
during sepsis pathogenesis [23].
Interleukin 4 (IL-4) is another cytokine in the immune
system arsenal that has immunosuppressive effects. This
cytokine is unique because during sepsis it is not released
systemically into the bloodstream. Studies have not been
able to detect changes in IL-4 plasma levels of septic
patients, however isolated splenocytes from septic mice
did secrete higher levels of this cytokine when stimulated
ex-vivo [23]. These results suggest a local effect of IL-4
immune suppression during a septic state, limiting its
therapeutic potential. IL-4 works by inhibiting Th1 cells
from polarizing and differentiating, as well as playing an
important role in B cell differentiation, thereby promot-
ing a Th2 mediated response [23]. IL-4 suppresses mac ro-
phage activity by preventing their cytotoxic activity,
parasite killing, and nitric oxide production [27,28].
Interleukin 13 (IL-13) shares many similar character-
istics to IL-4, from its gene location (close proximity to
IL-4 gene) to the receptor it activates (IL-4 type I recap-
tor) [27]. However, unlike IL-4, IL-13 has negligible
effects on Th2 cell function. IL-13 has been shown to
affect cell surface expression of different receptors in
macrophages and monocytes, such as up regulating the
expression of some integrins, while leaving other cell-
cell interacting receptors unaffected [29]. An important
mechanism by which IL-13 exerts its anti-inflammatory
properties is through the down regulation of CD-14 re-
ceptor expression. CD-14 is an important co-receptor wi th
Toll Like Receptor 4 (TLR4) that recognises lipopoly-
saccharide (LPS) and elicits a strong immune response
[29]. Furthermore, IL-13 also down regulates the expres-
sion of many pro-inflammatory cytokines such as TNFα
& IL-1 in monocytes [27]. Investig ations into the role of
IL-13 during sepsis indicate that mice show elevated lev-
els of IL-13, and anti-IL-13 antibody treatment reduces
their survival [27]. Interestingly, the anti-IL-13 antibody
treated mice showed an increased neutrophil influx into
tissues, but no effect on bacterial load and other leuko-
cyte infiltration. The excess neutrophil influx into tissues
showed an increase in organ damage indicating progres-
sion of the septic pathophysiology [27].
Transforming Growth Factor-β (TGF-β) has many reg u-
latory properties, therefore can have both pro and anti-
inflammatory properties. TGF-β modulates the activity
of other cytokines through either enhancing or antago-

I. Burkovskiy et al. / Advances in Bio science and Biotechnology 4 (2013) 860-865 864
nizing effects [27]. TGF-β can diminish the proliferation
and differentiation of T cells and B cells by blocking
production of specific cytokines like IL-2 [23]. Studies
comparing cytokine levels showed elevated systemic lev-
els of TGF-β in trauma patients bu t no significan t chang e
in patients with septic shock [23]. Studies with TGF-β
knockout mice showed an exaggerated inflammatory
reaction, indicating the anti-inflammatory properties of
this cytokine [27]. Furthermore, TGF-β can promote a
state of resolution and repair, opposing the effects of a
pro-inflammatory cascade similar to IL-4. These results
indicate a more local response of TGF-β, similar to IL-4,
limiting its therap eutic potential in systemic diseases lik e
sepsis [23,27] .
7. CONCLUSION
The mortality of severe sepsis and septic shock ranges
from 30% to 70% respectively. Clinically, there are only
very few treatments shown to be beneficial in sepsis, e.g.
antibiotics and vasopr essors [15]. There are many poten-
tial explanations fo r little to no impact of the o ther thera-
pies—such as the timing of the drug administration, sys-
temic levels of cytokines not always reflecting the patho-
logical picture and the immune status of the patient.
Currently there are reports in literature that indicate a
new potential focus on specific development of a clini-
cally applicable therapy that would utilize the immuno-
modulating properties of the endocannabinoid system to
combat the onset of sepsis [30,31]. The strategy of the
approach would be revolving around the condition when
the pro-inflammatory cytokine levels appear to be high.
In summary, the research in this field is highly important
in order to advance our understanding and to develop an
effective therapeutic strateg y.
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