Cytokines Induced During Influenza Virus Infection

Abstract

Influenza A virus is one of the major human pathogens. The influenza infection can pass out without any subclinical symptoms or infestation can appear in upper respiratory tract as well as in lower respiratory tract where it can result in lethal outcome. Both innate and adaptive immune responses are activated shortly after infection providing protection against infection. Many activities of the cells of innate and adaptive immunity are coordinated by cytokines. However, inordinate or disbalanced immune response may result in overproduction of cytokines as well as chemokines what can lead to severe inflammation, including excessive recruitment of neutrophils and mononuclear cells at the site of infection. These may damage lung tissue, reduce respiratory capacity, and cause severe disease and mortality. Recently, the role of cytokines induced by virus infection has been reevaluated. While moderate inflammatory response protects against development of severe illness, the hyper-inflammatory response can elevate the disease progression. In this minireview we summarized the data on cytokines and chemokines induced in the sera of hospitalized patients infected with human and avian high pathogenic influenza viruses and define their possible role in pathogenesis. Interleukine IL-6 and chemokines CCL-2/MCP-1, CCL-4, MIP/1β, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are associated with pathogenicity of both avian (H5N1 and H7N9) and human (pdmH1N1 and H3N2) viruses. Chemokines CCL-2/MCP-1, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are also connected with mortality. These cytokines may be used as targets for new, more complex therapy in the extenuation of unfavorable effects of hyper inflammatory response.

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REVIEW ARTICLE
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Cytokines Induced During Influenza Virus Infection
Tatiana Betáková1,2,*, Anna Kostrábová2, Veronika Lachová1 and Lucia Turianová1
1Biomedical Research Center - Slovak Academy of Sciences, Institute of Virology, Bratislava, Slovak Republic; 2Comenius University
in Bratislava, Faculty o f Natural Sciences, Departm ent of Microbiology and Viro logy, Bratislava, Slovak Republic
A R T I C L E H I S T O R Y
Received: January 27, 2017
Accepted: March 13, 2017
DOI:
10.2174/1381612823666170316123736
Abstract: Influenza A virus is one of the major human pathogens. The influenza infection can pass out without
any subclinical symptoms or infestation can appear in upper respiratory tract as well as in lower respiratory tract
where it can result in lethal outcome.
Both innate and adaptive immune responses are activated shortly after infection providing protection against
infection. Many activities of the cells of innate and adaptive immunity are coordinated by cytokines. However,
inordinate or disbalanced immune response may result in overproduction of cytokines as well as chemokines
which can lead to severe inflammation, including excessive recruitment of neutrophils and mononuclear cells at
the site of infection. These may damage lung tissue, reduce respiratory capacity, and cause severe disease and
mortality. Recently, the role of cytokines induced by virus infection has been reevaluated. While moderate in-
flammatory response protects against development of severe illness, the hyper-inflammatory response can elevate
the disease progression. In this mini-review, we summarized the data on cytokines and chemokines induced in the
sera of hospitalized patients infected with human and avian influenza viruses and define their possible role in
pathogenesis. Interleukin IL-6 and chemokines CCL-2/MCP-1, CCL-4/MIP-1β, CXCL-8/IL-8, CXCL-9/MIG,
and CXCL-10/IP-10 are associated with pathogenicity of both avian (H5N1 and H7N9) and human (pdmH1N1
and H3N2) viruses. Chemokines CCL-2/MCP-1, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 are also
related with mortality. These cytokines may be used as targets for new, more complex therapy in the extenuation
of unfavorable effects of hyper inflammatory response.
Keywords: Cytokines, chemokines, interferon, influenza virus, interleukin, immunity, pathogenesis, macrophage, NK cell, T cell, B cell.
1. INTRODUCTION
Influenza viruses cau se respirato ry infections and as widespread
pathogens endanger the human population. The severity of influ-
enza infection can range from asymptomatic infection to primary
viral pneumonia and death. Each year, about 500 million people are
infected and about 500 000 people die due to the influenza A virus
infection [1, 2]. Th e genome of viruses consists of eight RNAs with
negative polarity. Influenza A viruses are responsible for annual
epidemics and occasional pandemics. Understanding the immune
response to influenza viruses is crucial for interference during clini-
cal manifestation of influenza infection [3].
The innate immune response represents the first line of defense
against influ enza virus infection. Immune system recognizes the
infected cells by pathogen recognition receptors (PRRs) which are
present on each cell. PRPs recognize foreign molecular patterns
known as pathogen-associated molecular patterns (PAMPs). Upon
PAMP recruitment, PRRs trigger intracellular signaling cascades
inside the cell resulting in the expression of a variety of
proinflammatory molecules, which invite dendritic cells,
macrophages, neutrophils, NK cells, basophils and eosinophils to
the site of infection, induce production of int erferons to secure
antiviral activity, restriction of virus replication, spreading the
virus, and conduct the adaptive immune response [4]. The PRRs
include th e Toll-like receptors (TLR), RIG-like receptors and NOD-
like receptors. The TLRs are expressed in most cells where they are
present within endosomal compartments or on the cell surface [4].
Activation of cytosolic melanoma differentiation- associated gene 5
(MDA-5) or retinoic acid-inducible gen e I (RIG-1) leads to
*Address correspondence to this author at the Biomedical research Center,
Institute of Virology, Dubravska cesta 9, 845 05 Bratislava, Slovak
Republic; Tel: 00421-2-59 302440; Fax: 004 21-2-54774284;
E-mail: virubeta@savba.sk
interaction of the caspase activ ation and recruitment domains
(CARDs) with CARD of the mitochondrial activator of virus sig-
naling (MAVS) protein, when RLRs are the signaling adapter pro-
teins [5, 6].
CARD-CARD interactions activate TBK1 and IKKɛ protein
kinases which are responsible for phosphorylation of the transcrip-
tion factors interferon regulatory factor (IRF ) 3 and nuclear factor
κB (NF-κB). The tumor necrosis factor receptor type 1-associated
death domain (TRADD), Fas-associated protein with death domain
(FADD), receptor interacting protein 1 (RIP1), caspase-8, and
caspase-10 activate IKKα, IKKβ, and IKKγ proteins which create
the IKK comp lex, the fundamental element of th e NF-κB cascade
[4, 5, 7]. A ctivated IRF3 and NF -κB are then transported from the
cytosol into the nucleus where they turn on genes responsible for
regulation of inn ate immunity, including interferons (IFNs) an d
proinflammatory genes. IFNs activate hundreds of interferon-
stimulated genes (ISGs) and ensure antiviral, metabolic regulatory,
cell growth regulatory, and immunomodulatory actions [4, 8].
Uncontrolled inflammatory response to virus in combination
with viral virulence can lead to severe lung devastation [9, 10].
Therefore, it has been broadly suggested that disease severity de-
pends on the amount of cytokines released during a cytokine storm
in response to influenza infection [2, 11].
2. ROLE OF CYTOKINES DURING INFLUENZA VIRUS
INFECTION
Cytokines are a large group of secreted proteins with diverse
structure and functions, which regulate and coordinate many activi-
ties o f the cells of innate and adaptive immunity. Cytokine is
a general name for the group of small proteins that include lym-
phokines (cytokines made by lymphocytes), monokines (cytokines
made by monocytes), chemokines (cytokines with ch emotactic
activities), interleukins (cytokines mad e by one leukocyte and act-

2 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Betáková et al.
ing on other leukocytes), and interferons (cytokines, which interfere
with viral infection).
Viral antigens are recognized by dendritic cells (DC), macro-
phages, and T cells in subepithelial tissues which produce Th1-
polarized proinflammatory cytokines, IFN–γ and tumor necro sis
factor (TNF-α). These cytokines induce production of chemokines
and other molecules responsible for host defense. The presence of
conserved NH2- terminal cysteine residues assigns chemokines into
4 groups: CC, XC, CXC and CX3C [12]. There are 28 known CC
chemokine ligands (CCL1-CCL28) which induce the migration of
monocytes, dendritic cells, T cells and other leukocytes. Monokines
induced by IFN-γ CXCL9/M IG, IFN-inducible protein CXCL10/
IP-10 and IFN-inducible T cell α-chemoatt ractant CXCL11/I-TAC
belong to the group of CXC chemokines [13-15]. The activity of
these chemokin es is closely associated with CXC chemokine recep-
tor 3 (CXCR3) located on the surface of T cells and natural killer
(NK) cells [16]. Fractalkine, the only member of CX3C group, ser-
ves as a chemoattractant as well as an adhesion molecule. The last
subfamily includes two chemokines, lymphotactin a and b,
expressed predominantly in activ ated T cells. All cells of immune
system secrete at least some cytokines with diverse structures and
functions.
2.1. Cytokines Associated with Complicated Influenza in
Humans
Moderate inflammatory response protects against development
of severe illness and hyper-inflammatory response support the
negative disease development. Many studies focusing on influenza
H1N1 pdm09 found out that disease severity was strongly associ-
ated with high level of circulating interleukin IL-6, IL-10, IFN-γ-
induced protein (CXCL10/IP-10) and monocyte chemotactic pro-
tein-1 (CCL2/MCP-1) [17]. In symptomatic individuals, the major
cytokine which undergoes the earliest increase is IL-6. Later during
infection, the level of CXCL10/IP-10 and CCL2/MCP-1 is in-
creased which suggests that these cytokines play important role in
early pathology development. Afterwards, a number of other cyto-
kines, such as T helper type I (Th1) cytokines IFN-γ, IL-15, and
chemoattractant IL-8, begin to be expressed significantly [18, 19].
Inflammation induced by influenza virus is connected to influenza
virus-associated encephalopathy (IE). IL-1β, IL-2, IL-6, IL-7, IL-8,
IL-10, IL-13, granulocyte colony stimulating factor (G-CSF),
granulocyte macrophage colony-stimulating factor (GM-CSF),
TNF-α, metallopeptidase inhibitor 1 (T IMP-1), matrix metallopep-
tidase 9 (MMP-9), sE-selectin, and neutrophil elastase were ele-
vated significantly in sera from patients with uncomplicated influ-
enza and those with IE. N eutrophil elastase, sE-selectin, IL-8, and
IL-13 were significantly increased in IE when compared with un-
complicated influenza [19]. Concentrations of IL-6, IL-10, IL-15,
CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, IL-2R, hepatocyte
growth factor (HGF), ST2, CCL2/MCP-1, CCL4/MIP, and soluble
tumor necrosis factor receptors 1 (sTNFR-1) were significantly
higher in patients with severe influenza H1N1 pdm09 virus infec-
tion [18]. Distinct changes for IFN-α2, CCL7/MCP-3, IL-6, vascu-
lar endothelial growth factor A (VEGFA) in nasal washes and
CCL7/MCP-3, IL-10, and CXCL10/IP-10 in peripheral blood of
human patients correlated significantly with disease severity and
did not depend on the virus load [20]. Elevated proinflammatory
cytokines, particularly IL-6, predicted ICU admission and corre-
lated with fever, tachypnoea, deoxygenation, and length of stay
during influenza infections [17, 21, 22].
Elevated levels of CXCL10/IP-10, IL-6, IL-17, and IL-2 were
detected in sera of 16 hospital-admi tted patients infected with
H7N9 virus [23, 24]. Recent studies confirm correlation between
levels of cytokines in serum: macrophage migration inhibitory fac-
tor (MIF), stem cell factor (SCF), CCL2/MCP-1, CCL2/MCP-1,
HGF, and mast/stem cell growth factor beta (SCGF-β) and disease
severity after H7N9 infection [25]. The increased expression of
proteins associated with the recruitment and activation of memory
T cells, such as CXCL11/I-TAC, CXCL10/IP-10, IL-16 and granu-
lysin (GNLY) was detected in n asal washes [14, 26-29].
The levels of CXCL10/IP-10, IL-2, IL-6, IL-17 were elevated
in the individuals infected with influenza H7N9 [23, 30].
High levels of inflammatory cytokines in the peripheral blood,
including CXCL10/IP-10, CCL2/MCP-1, monokine induced by
IFN-γ (CXCL9/MIG) and CXCL8/IL-8 were detected in patients
who died due to avian influenza A virus (H5N1) infection. Other
research findings suggest that modulation of the inflammatory
pathway can be used in adjunctive therapies [3, 31-33]. Influenza
infection with H5N1 virus induces activation of chemoattractants
CXCL10/IP-10, CCL2/MCP-1, CCL4/MIP-1β, CXCL9/MIG, and
CXCL8/IL-8, which are driven by adaptive and innate responses.
The induction of certain proinflamm atory cytokines, such as TNF-α
and chemoattractans CXCL10/IP-10, CCL4/MIP-1β, CCL2/MCP-
1, and CXCL9/MIG is closely bound with pathogenesis of severe
H5N1 and H3N2 influenza infections [31, 32, 34, 35].
Expression of mitogen-activated protein kinases (MAPKs) and
c-Jun N-terminal kinases (JNKs), which play a role in the immune
response to avian and human influenza infection, was reduced in
sera from influenza infected patients versu s healthy controls [24].
2.2. Type I and Type III Interferons Determine the Course of
Infection
Anti-viral protection in mammals is substantially supported by
type I and type III IFNs. Both IFN-α/β and IFN-λs signal through
their receptors and activate the same pathway which results in the
formation of a ternary transcription complex: STAT1, STAT2 and
IFN regulatory factor-9 (IRF9), known as IFN-stimulated gen e
factor 3 (ISGF3) [36-38]. The type I IFNs receptor complex con-
sists of two chains, IFNAR1 (IFN-αR1) and CD118 (IFN-αR2),
type III IFNs heterodimeric receptor contains unique IFNLR1 (IFN-
λR1) and CD210B (IL10R2) chains [36, 39, 40]. The CD210B
serves as the second subunit for IL-10, IL- 22, and IL-26 [36]. The
expression of IFN-λ receptors is restricted to a subset of cells, pri-
marily epithelial cells, keratinocytes, some dendritic cells and neu-
trophil population [38, 41-45]. Activity of type I and type III IFNs
differs in rapidity and specificity. Type I IFNs induce greater and
faster response than type III IFNs. On the other hand, activity of
type III IFNs emerges later, but induction is more permanent [46-
48].
Type I IFNs activate ISGs promoters by binding of IRF and
other transcription factors to interferon–stimulated response ele-
ment (ISRE). Antiviral signaling of type III IFNs is connected to
activation of NF-κB and MAPK [49]. The type III IFNs rely
strongly upon both p38 and JNK MAP kinases for gene induction
[46, 50]. Transcription factor Med23 selectively upregulates type
III but not type I IFN signaling, and type III IFNs are specifically
downregulated by ZEB1 [49, 51,52].
The main antiviral action of IFNs lies in inhibition of viral rep-
lication and induction of the immune response elicited by viruses
[53-59]. However, recently, it has been shown that IFNs cause im-
munopathology in some acute influenza virus infections. Type I
IFNs appear to influence the role of several immune functions dur-
ing superinfection. These IFNs have been implicated in the d evel-
opment of Staphylococcus aureus and Streptococcus pneumoniae
superinfection [60, 61]. The IFNs are associated with suppression
of Th17 and production of peptides with antimicrobial activities,
which increase risk for both gram-positive and gram-negative bac-
terial coinfection during influenza infection [61]. The activity of
type I IFNs results in decreased amount of CCL2/MCP-1 and inhi-
bition of IL-17 [62-64]. It seems that the proinflammatory response
initiated by RIG-1 and TLR7 plays positive role in influenza virus
replication. After TLR7 and RIG-1 signaling, monocyte derived
DCs are accumulated in the lungs where they can be infected by the

Cytokines Induced during Influenza Virus Infectio n Current Pharmaceutical Design, 2017, Vol. 23, No. 00 3
virus [65]. The type III IFNs facilitate infection of lower respiratory
tract. In a model of post-influenza acute Staphylococcus aureus
lung infection, wild type mice infected with influenza were more
susceptible to bacterial infection due to production of type III IFNs
in the lungs [66].
2.3. The IFN-γ as a Major Player of Innate and Adaptive
Immunity
The type II IFN (IFN-γ) is expressed by certain cell types,
namely NK, T cells and natural killer T cells (NKTs). The biologi-
cal activity of IFN-γ is induced after binding to its receptor, which
consist s of two ligand binding CD119 (IFN-γR1) chains and two
signal-transducing IFNGR2 (IFN-γR2) chains. The activation of
this signaling pathway involves the binding of IFN -γ to form the
IFN-γR complex [67]. Each IFN-γR subunit binds to JAK1 and
JAK2 complex, where N-terminal domains are activated by tyrosine
phosphorylation [67-69]. Activated JAK1 and JAK2 are responsible
for phosphorylation of the IFN-γR tails. The phosphorylated recep-
tor binds the STAT1 monomers via their src-homology 2 domains.
After phosphorylation by JAKs, STAT1 monomer dissociates from
the receptor and as STAT1:STAT1 homodimer is transported to the
nucleus. Binding of the STA1:STAT1 homodimer with γ-activated
sequence (GAS) elements activates the promoters of IFN-γ respon-
sive genes [68]. IFN-γ can also stimulate STAT3 and STAT5 [70,
71].
The IFN-γ induces the expression of: i) proteins with antiviral
activities (PKR, OAS, and Mx GTPase); ii) enzyme which impairs
translation of viral proteins: dsRNA-specific adenosine deaminase
(ADAR); iii) type I IFNs; and iv) proinflammatory cytokines and
chemokines by endothelial cells and fibroblasts which invite
macrophages, neutrophils and T cells to the site of infection [72].
IFN-γ affects the local cellular response in the respiratory tract as
well as the systemic humoral response to influenza virus infection
[73]. However, IFN-γ deficiency does not influence the elimination
of influenza virus, suggesting that IFN-γ may primarily function to
modulate severity of disease caused by influenza infection [74].
Influenza infection results in serious lung damage facilitated by
CD8+ T cell effector functions. Recently, it was identified that IFN-
γ signaling and STAT1-independen t IFN-γ signaling have impor-
tant roles in regulating CD8+ T cell-mediated acute lung injury
[75]. The IFN-γ regulates local immunity against virus infection by
reducing antigen-specific CD8+ T cells and inhibiting memory pre-
cursor form ation. By this mechanism, IFN-γ reduces th e population
of the memory cells after an influenza virus infection [76]. The
relatively high levels of IFN-γ in the lung following influenza
caused inhibition of MARCO expression, which is essential for
phagocytosis of bacteria. Thus, alveolar macrophage–mediated
clearance of S. pneumoniae is significantly inhibited by prior influ-
enza virus infection [77].
CONCLUSION
The exact functions of cytokines in immune response to influ-
enza virus infection are yet to be determined. Recent data proved
that the cytokine levels correlate with disease severity. High ex-
pression of cytokines does not need to depend on virus load [20].
Here, we briefly reviewed the overexpression of cytokines which is
associated with disease severity and mo rtality. Table 1 summarizes
the available data on the principal cell source and cellular targets
and biological effects of these cytokines during common infection
with influenza virus.
We are aware that this table does not provide comprehensive
information about all cytokines enhanced during influenza infec-
tion. The human’s experiments with in fluen za viruses are restricted
and most of the available data were obtained from the patients and
from post mortal analyses. In most studies, the age of patients is
missing. Nevertheless, the level of some cytokines were raised in
children as well as in adults and increased level of these cytokines
always correlated with disease severity [3, 9, 19]. Interleukin IL-6
and chemokines CCL-2/MCP-1, CCL-4/MIP-1β, CXCL-8/IL-8,
CXCL-9/MIG, and CXCL-10/IP-10 are associated with pathogenic-
ity of avian and human viruses (Fig. 1). Interestingly, chemokines
CCL-2/MCP-1, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10
are connected with mortality and these chemokines regulate T cell,
macrophages, neutrophils, basophils and NK cells function and
recruitm ent (Table 1). Expression of these cytokines can be mis-
regulated also by the influenza viruses. The multifunctional non-
structural protein 1 (NS1) suppresses the antiviral host defence by
affecting interferon responses and enhances virus pathogenesis
[78]. Virus replication, pathogenicity and innate immune response
can also be influenced by PB1-F2 and PB2 proteins [79-82]. The
PB1-F2 protein inhibits induction of type I IFNs and NK cells and
influences neutrophil recruitment resulting in increased viral patho-
genesis [83, 84]. The role of viral proteins in immune response is
started to be extensively studied.
Table 1. Selected cytokines associated with severe infection and their primary activities. Cytokines whose overproduction is linked to
mortality are in bold.
Cytokine
Principal Cell source
Cellular targets and biologic effects
Negative role during influenza infection
IL-2
T cells
induces expansion of antigen-specific clones of T
cells; augments cytokine production by T cells and
NK cells; enhances antibody secretion by B cells
H1N1 pdm09 - associated with d isease severity [2] and
encephalopathy [19];
H7N9 - associated with d isease severity [23,24];
IL-6
macrophages, endothe-
lial cells, T cells, B cells
proliferation of antibody producing cells; develop-
ment or inhibition of defined effector T cell popula-
tions;
synthesis of acute-phase proteins
H1N1 pdm09 - associated with d isease severity
[17,18,20] and encephalopathy [19]; pathology devel-
opment [18]; correlates with fever, tachypnoe and
deoxygenation [17,21,22]
H7N9 - associated with d isease severity [23,24];
IL-10
macrophages, mast
cells, B cells, T cells
(regulatory)
downregulates expression of class II MHC and
costimulatory molecules on macrophages and den-
dritic cells;
stimulatory to mast cells and T cells; promotes B
cell maturation
H1N1 pdm09 - associated with d isease severity [17,18,
20] and encephalopathy [19];

4 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Betáková et al.
(Table 1) Contd....
Cytokine
Principal Cell source
Cellular targets and biologic effects
Negative role during influenza infection
IL-13
CD4+ T cells (TH2),
NKT cells, mast cells,
group 2 innate lymphoid
cells
isotype switching and IgE production by B cells; increases
mucus production by epithelial cells and collagen synthesis
by fibroblasts;
alternative activation of macrophages
H1N1 pdm09 - associated with encephalopa-
thy [19];
IL-15
macrophages, dendritic
cells,
other cell types
survival and proliferation of memory CD8+ cells;
augments B cell and NK cell proliferation
H1N1 pdm09 - associated with d isease sever-
ity [18]
IL-16
CD4+ and CD8+ cells,
epithelial cells
modulator of T cell activation;
stimulates migration of CD4+ lymphocytes, monocytes and
eosinophils
H7N9 - associated with d isease severity [14,
26-29];
IL-17
T cells
potent activator of neutrophils;
induces neutrophil and monocyte inflammatory response;
H7N9 - associated with d isease severity
[23,24];
SCF
(MGF)
stem cells
Stimulates the survival and p roliferation o f myeloid,
erythroid, and lymphoid progenitors in bone marrow cul-
tures; indu ces differentiation of mast cells
H7N9 - associated with disease severity [25]
HGF
stromal cells,
mesenchymal cells
stimulates proliferation, motility, morphogenesis and angio-
genesis of epithelial cells
H1N1 pdm09 - associated with d isease sever-
ity [18];
H7N9 - associated with d isease severity [25]
SCGF-β
mast cells,
stem cells
growth factor for primitive hematopoietic progenitor cells
H7N9 - associated with d isease severity [25]
MIF
macrophages, T cells,
dendritic cells, endothe-
lial cells, eosinophils
promotes migration and recruitment of immune cells;
induces proinflammatory cytokines; regulates macrophage
function
H7N9 - associated with d isease severity [25]
IFN-α/β
plasmacytoid dendritic
cells,
macrophages, endothe-
lial cells, NK cells, B
and T cells, fibroblasts
induces anti-viral state in cells;
increases class I MHC expression; regulation of anti-viral
response by T cells;
activation of NK cells and B cells; stimulation of macro-
phages
H1N1 pdm09 - associated with d isease sever-
ity [20];
suppression of Th17 [61];
decreasing of CCL2 and IL-17 [62-64]
IFN-γ
T cells (TH1, CD8+ T
cells)
NK cells
increased expression of class I and II MHC molecules, en-
hanced antigen processing and presentation to T cells; classi-
cal macrophage activation (increased microbicidal func-
tions); promotes activity of NK cells and TH1 differentiation
reduction of CD8+ T cells in lung [75];
reduction of the memory cells population
[76];
inhibition of MARCO expression [77]
IFN-λ
dendritic cells
induces anti-viral state
facilitate infection of lower respiratory tract
by bacteria [66]
TNF-α
macrophages, CD4+ T
cells, NK cells, neutro-
phils, mast cells, eosi-
nophils, neurons
regulation of cell proliferation, differentiation, apoptosis,
lipid metabolism and coagulation; stimulation of endothelial
cells, T cells, neutrophils;
macrophage differentiation;
regulation of B cell function
H1N1 pdm09 - associated with encephalopa-
thy [19]
CCL2
(MCP-1)
monocytes, macro-
phages, dendritic cells
development of polarized Th2 responses; mixed leukocyte
recruitment;
chemotactic activity for dendritic cells, monocytes and baso-
phils
H1N1 pdm09 - associated with d isease sever-
ity [17,18]
H3N2 - associated with p athogenicity [31, 32,
34, 35]
H7N9 - associated with d isease severity [25];
H5N1 – associated with p athogenicity [31, 32,
34, 35] and mortality [3, 31-33]

Cytokines Induced during Influenza Virus Infectio n Current Pharmaceutical Design, 2017, Vol. 23, No. 00 5
(Table 1) Contd....
Cytokine
Principal Cell source
Cellular targets and biologic effects
Negative role during influenza infection
CCL4
(MIP-1β)
macrophages,
CD8+ T cells
T cells, dendritic cells, monocytes and NK cells
recruitment
H1N1 pdm09 - associated with disease severity [18];
H3N2- associated with pathogenicity [31,32,34,35];
H5N1 - associated with p athogenicity [31,32,34,35]
CCL7
(MCP-3)
macrophages, tumor cell
lines
mixed leukocyte recruitment;
regulates acute neutrophilic lung inflammation
H1N1 pdm09 - associated with d isease severity [20]
CXCL8
(IL-8)
macrophages, epithelial
cells,
endothelial cells
mediator of inflammatory response; attracts neutro-
phils, basophils, and T-cells;
regulates macrophages, endothelial cells and mast
cells function
H1N1 pdm09 - associated with d isease severity [18]
and encephalopathy [19];
H5N1 – mortality [3, 31-33]
CXCL9
(MIG)
alveolar macrophages
IFN-induced T cell chemoattractant; affects the
growth, movement or activation state of cells that
participate in immune and inflammatory response
H1N1 pdm09 - associated with d isease severity [18];
H3N2 - associated with p athogenicity [31,32,34,35]
H5N1 – associated with p athogenicity [31,32,34,35]
and mortality [3,31-33]
CXCL10
(IP-10)
alveolar macrophages,
monocytes, endothelial
cells, fibroblasts, other
cell types
effector T cell recruitment; chemotactic for T cells,
macrophages and dendritic cells;
stimulation of monocytes, NK cells and T cell mi-
gration, and modulation of adhesion molecule ex-
pression
H1N1 pdm09 - associated with d isease severity [17,
18, 20]; pathology developm ent [18,19];
H3N2 - associated with p athogenicity [31, 32, 34, 35]
H7N9 - associated with d isease severity [14, 23, 24,
26-29];
H5N1 – associated with p athogenicity [31,32,34,35]
and mortality [3,31-33]
CXCL11
epithelial cells, thyro-
cytes, peripheral blood
leukocytes
Recruits T cells, NK cells and macrophages to the
site of inflammation
H7N9 - associated with d isease severity [14, 26-29]
Fig. (1). Cytokine associated with severity and mortality of both avian and human influenza viruses. Several different cell types coordinate their effort as
part of immune system during influenza infection. Macrophages, dendritic cells, B cells, T cells NK cells, endothelial cells, mast cells, neutrophils, basophils
and eosinophils have distinct roles in immune system using secreted cytokines.

6 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 Betáková et al.
Better understanding of the interaction between virus, tissue
and immune response may help in better diagnostic and prognoses
during severe acute influenza infection. One of the possible future
approaches to extenuate the unfavorable effects of hyper inflamma-
tory response may also focus on targeted control or reduction of the
level of cytokines which are linked to mortality.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
This research was supported by the Slovak Research and De-
velopment Agency, grant No. APVV-0676-12, by the Scientific
Grant Agency of the Slovak Republic VEGA No. 2/0014/16.
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