The role of Interleukin-6 (IL-6) in pathogensis of COVID -19

Abstract

Dissimilar to all other pandemics in the past five decades, the humanity has been ravaged by the coronavirus disease COVID-19. Starting from its outbreak, the disease's understanding has advanced quickly; multi-organ involvement is the key factor affecting the prognosis of the disease. Mortality and morbidity are closely related to acute respiratory distress syndrome, renal failure, cardiac failure, liver damage, multi-organ failure, and shock. In the initial phases of viral infection, detecting and controlling pro-inflammatory responses are essential. Throughout patient monitoring, it is crucial to consider the COVID-19 treatment's unknowable response. It has been discovered that interleukin-6 (IL-6) is causally linked to greater mortality. It is a reliable indicator regarding the progression of clinical profile as well as the prognosis of the disease. A highly important cytokine, after the activated macrophages, is it. As a result, a measure for COVID-19 could be the control regarding systemic IL-6 levels in the individuals that have been infected by SARS-CoV-2. This study has demonstrated the significance of IL-6 in COVID-19's immunopathology.

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University of Thi-Qar Journal of Science (UTJsci)
E-ISSN:2709-0256, ISSN Print: 1991-8690 Volume (10), No.1 June 2023
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This work is licensed under a Creative Commons Attribution 4.0 International License.
https://doi.org/10.32792/utq/utjsci/v10i1.895
1
The role of Interleukin-6 (IL-6) in pathogensis
of COVID -19
Noorulhuda F. Khalaf
Tropical Biological Research
Unit/College of Science/ University
of Baghdad
Baghdad/ Iraq
https://orcid.org/0000-0001-9958-
1797
Sinai W. Mohammed
Tropical Biological Research Unit
/College of Science/University of
Baghdad
Baghdad/ Iraq
https://orcid.org/0000-0001-8359-
4921
Ahmed Y. Hanoon
Tropical Biological Research
Unit/College of Science/University
of Baghdad
Baghdad/ Iraq
Abstract---Dissimilar to all other pandemics in the past five
decades, the humanity has been ravaged by the coronavirus
disease COVID-19. Starting from its outbreak, the disease's
understanding has advanced quickly; multi-organ involvement
is the key factor affecting the prognosis of the disease. Mortality
and morbidity are closely related to acute respiratory distress
syndrome, renal failure, cardiac failure, liver damage, multi-
organ failure, and shock. In the initial phases of viral infection,
detecting and controlling pro-inflammatory responses are
essential. Throughout patient monitoring, it is crucial to
consider the COVID-19 treatment's unknowable response. It
has been discovered that interleukin-6 (IL-6) is causally linked
to greater mortality. It is a reliable indicator regarding the
progression of clinical profile as well as the prognosis of the
disease. A highly important cytokine, after the activated
macrophages, is it. As a result, a measure for COVID-19
could be the control regarding systemic IL-6 levels in the
individuals that have been infected by SARS-CoV-2. This
study has demonstrated the significance of IL-6 in COVID-
19's immunopathology.
Keywords: COVID-19, Cytokines, IL-6, Pathogenesis
I. INTRODUCTION
A respiratory infection is brought on by coronaviruses,
members of the Coronaviridae family, in both avian and
mammal species, including camels, bats, and masked palm
civets (1). Diverse host species may exhibit
various coronavirus infection symptoms as well as tissue
tropism (2). Human coronavirus infections can be
asymptomatic or come with symptoms like coughing,
fever, stomach discomfort, and shortness of breath (3). In
some situations, especially in immunocompromised and
old people, coronavirus infections can cause severe
pneumonia and ultimately the patient's death (4). The
WHO designated COVID-19, which is caused by SARS-
CoV-2, as pandemic on March 11th, 2020. All over the globe,
about 496 million confirmed cases and more than 6 million
fatalities were documented as of 10 April 2022 (5). SARS-
CoV-2 can be defined as a brand-new coronavirus strain
which hasn't been found in the humans before. SARS-CoV-2
may have evolved from the zoonotic cycle and expanded
quickly through human-to-human transmission, according to
phylogenetic study (6). Cytokines are thought to be crucial in
controlling and treating coronavirus infections
throughout SARS-CoV-2 infection. Yet, unchecked and
excessive cytokine production can cause tissue damage
across the whole human body, which can result in
immunopathogenesis (7). Patients with COVID-19 will
experience some mild to moderate symptoms, however a
few infected individuals could experience cytokine release
syndrome (CRS), which is a hyper-inflammation that is
brought on by large cytokine/chemokine production that can
cause deadly pneumonia and acute respiratory distress
syndrome. An essential cytokine, IL-6 is associated with a
number of inflammatory disorders. High amounts of IL-6
were found in SARS-CoV-2-infected subjects, and these
levels have been linked to patient symptoms like severe lung
damage and pulmonary inflammation (8). Patients who had
SARS-CoV2 also exhibited low levels of cytokine signaling-
3suppressor that controls and boosts IL-6's negative feedback
mechanism (9). In the same line, another research found that
severe COVID-19 patients had greater IL-6 levels, and this
could be one of bases to predict change from a mild infection
to severe one (10).
II. PATHOGENESIS of SARS-CoV-2
Understanding the pathogenesis of COVID-19, which is
spreading quickly and causing significant morbidity and
mortality all over the world, will be crucial for managing it.
The primary receptor for SARS-CoV-2 is angiotensin-
converting enzyme 2 (ACE2), which is found in vascular,
respiratory epithelium, macrophages, and alveolar
monocytes. Another significant COVID-19 pandemic
symptom was lymphopenia. The loss of CD8 and CD4 cells,
a hallmark of SARS-CoV-2 patients, frequently came before
the disease's radiographic manifestations. Unknown

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mechanisms underlie the increasing lymphopenia in patients
with critical and severe COVID-19. According to studies,
increased mortality in patients with this disease is associated
with a lower lymphocyte count and higher ferritin, D-dimer,
and IL-6 levels. The three phases of the SARS-CoV-2
infection's clinical course include the viremia phase, the
acute phase (pneumonia), and the severity or recovery
phases. The early interventions have mostly been centered on
the proper timing of disease phases and the implementation
of strategies to halt or decrease the progression in COVID-19
patients. The steps in viral entry, replication, and appearance
of viral protein (spike protein) on the host cell surface
facilitated activation of the innate immune system through
inflammatory signaling pathways such as cytokine
production and programmed cell death (11, 12) (Fig.1).
Figure 1: Hypothetical pathogenesis of COVID-19 [11].
III. CYTOKINES & COVID-19
The interesting point in COVID-19 patients is the
cytokine storm. Patients with COVID-19 who had more
severe disease showed high levels of inflammatory
cytokines, which were linked to lung damage, pulmonary
inflammation, and multiple organ failure (13). The increase
in serum levels of pro-inflammatory cytokines like IL6,
IL1, IFN, IL12, MCP1, and IP10 was linked to pulmonary
inflammation in SARS patients, according to prior
research [14]. activated T-helper-1 (Th-1) cell response is
likely the result of increased IFNγ, IL1-β, IP-10, and MCP-1
levels in ICU COVID-19 patients, according to Huang et al.
report (15). Additionally, Diao et al. discovered a correlation
between severity of COVID-19 and TNF-α, IL-10, and IL-
6levels (16).
IV. INTERLEUKIN-6 (IL-6)
One of the major key mediators regarding inflammation
and viral cytokine storm in COVID-19 patients is IL6 (17).
Also, IL-6 can be defined as a cytokine that regulates
cell differentiation and proliferation as well as the immune
response. A 28-amino-acid signal peptide makes up part of
the 212 amino acids . The human IL-6 gene is located on
chromosome 7p21. A cytokine called IL-6 has both anti- and
pro-inflammatory characteristics. Additionally, IL-6
secretion has been linked to a number of other diseases and
conditions, including Alzheimer's, atherosclerosis, multiple
myeloma, systemic lupus erythematosus, autoimmune
deficiency disease, rheumatoid arthritis, chronic
inflammatory disease, and various cancers. Thus,
throughout disease, particularly their activation
following immune response triggering, control of IL-6
secretion has been found to be especially crucial (18, 19).
A. SOURCES OF IL-6 PRODUCTION
Numerous types of cells, which include the macrophages,
fibroblasts, T cells, endothelial cells, and monocytes, release
IL-6 (20). The T cells, B cells, eosinophils, basophils, and
neutrophils are targets of IL6. The differentiation regarding β
cells and the production of IgE, IgM, and IgA are two
activities of IL-6 on the β cells. IL-6 also regulates
differentiation, survival, and activation of the T cells. In
response to interleukin, leukocytes are activated. Thus,
cytokine storm after infection results in B and T cell
differentiation and activation. Cancers with poor prognoses
or cancer that has spread to other organs have higher levels
of IL-6. IL-6 secretion increases auto-antibody hyper gamma
globulinemia and induces B cells to produce antibodies. IL-6
also results in autoimmunity, chronic inflammation, CD-4
positive T-cell activation that promotes the differentiation of
theTh-17, and the CD-4 positive T-cell inhibition that
prevents the differentiationof the Treg (21).
B. IL-6 AND VIRAL INFECTIONS
Following viral infection, viral products promote the
translation or transcription of IL-6 as well from the cells
like mesenchymal, fibroblast, endothelial, and various other
cell types. Inhibition of IL6's signal that impacts cells could
thus depend on the control of IL6 secretion and synthesis.
Negatively regulating the IL-6 transcription also involves
using techniques that suppress IL-6 expression (22, 23).
Following viral infection, the activation regarding IL-6 and
the release of additional cytokines results in a fatal immune
response to the hyper-activation of the T cells. The similar
cytokine storm is seen as well following cancer treatment as
a result of the activation of the T-cells and an increase in the
secretion of the IL-6. As a result, it is believed that
pathological IL6 secretion is to blame for clinical symptoms
that follow a severe disease (24).
C. IL-6 IN PATHOGENESIS OF COVID -19
The link between the levels of IL-6 and virus
pathogenicity can be seen in the systemic elevation of IL6
throughout acute stage of the viral infections. Pleotropic
cytokine IL-6 is generated in response to the tissue injury and
infections. Additionally, compared to virus-negative groups,
human patients with virus infections had higher levels of
circulating IL-6, MCP-1 and TNF-α (25, 26). Due to the fact
that secretion of IL-6 that is produced from several types of

3
cell begins the activation pathway of the JAK/STAT3, it
leads to the promotion of numerous factors of transcription
that are related to the processes of the cellular
signalling. Due to the fact that it regulates monocyte
differentiation to macrophages, boosts the production of the
β-cell IgG, and promotes Th-2 response through suppressing
the polarization of theTh1, IL6 has been regarded as a very
crucial cytokine throughout an infection (27). Since IL-6
production was linked to both anti- and pro-inflammatory
effects, more research is required to understand how IL-6
mediates the cellular response to the viral infections,
particularly coronavirus.
D. IL-6 AS POTENTIAL THERAPEUTIC TARGET FOR
COVID -19
Depending on its ability to block cytokine storms, a
few works have suggested that humanized monoclonal
antibody against the IL6 receptors, tocilizumab, could be
utilized in the treatment of coronavirus (28). Tocilizumab
can be defined as an IL-6 receptor antagonist utilized for
treating CRS (29). In 21 patients with severe COVID-19
infection, one of the recent retrospective Chinese studies had
found that the tocilizumab reduced fever, hypoxemia, and
levels of CRP without having any severe negative effects
(30). Tocilizumab might just be administered to COVID-19
patients that are at the end of phase of high viral load, have
severe respiratory failures, interstitial pneumonia, and high
levels of lL6 and/or C-reactive protein/D-
dimer/fibrinogen/ferritin, according to Italian
recommendations (31). Cytokine storm can be treated with
immunosuppressants and corticosteroids, and it is systemic in
patients with COVID-19. Using hydrocortisone, however,
has been linked to COVID-19 patients' slower viral clearance
and a greater plasma SARS-CoV2 viral load, according to
recent investigations (32).
V. CONCLUSION
Clinical practice must constantly take into account IL-6's
crucial function in host defense. For patients with a variety of
clinical symptoms, different algorithms are utilized
throughout COVID-19 therapy. Yet, it is unclear how the
treatment will react to the cytokine storm, particularly the
release of IL-6. Increased systemic IL-6 levels must be
required to determine a higher probability of disease
deterioration based on COVID-19 severity. As a result,
targeting IL-6 treatment for patients who have been tested
positive for COVID-19 or monitoring IL-6 levels could be a
new effective treatment target.
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