4.1. IL-6
IL-6 plays multiple biological roles, which include enhancing the
synthesis of inflammatory response proteins, such as C-reactive protein
(CRP), regulating both T and B immune cells to increase immune
responses, and promoting the production of vascular endothelium growth
factor (VEGF), which aggravate the inflammatory damage by inducing
angiogenesis and impairing the vascular integrity. In addition to its
immune and inflammatory regulatory activities, IL-6 also upregulates the
activation of the coagulation pathway, increasing the thrombotic events
(D’Alessandro et al., 2020).
The proinflammatory function of
IL-6 is mediated through a series
of cell signaling pathways. IL-6 binds to its receptor (IL-6R) to
initiate intra cellular signaling. Two forms of IL-6R have been
found: membrane IL-6 receptor (mIL-6R) and soluble IL-6 receptor
(sIL-6R). The binding of IL-6 to both receptor results in the
dimerization and activation of the glycosylated type I membrane protein
of 130–150 kDa (gp130). IL-6/mIL-6R medicated activation of gp130
induces IL-6 classic signaling pathway; while IL-6/sIL-6R induced the
activation of gp130 leads to activation of IL-6 trans-signaling pathway
(Ebihara, Matsuda, Nakamura, Matsuda & Murakami, 2011). Classic IL-6
signaling is generally regarded as anti-inflammation and protective
pathway, while IL-6 trans-signaling is mainly pro-inflammatory pathway
(Garbers, Aparicio-Siegmund & Rose-John, 2015). Blockade of IL-6
trans-signaling, not the full blockade of IL-6 signaling, prevents
inflammation (Barkhausen et al., 2011).
The dimerization of signaling receptor gp130 mediates the activation of
Janus kinases (JAKs) and subsequent activation of phosphatase Src
homology domains containing tyrosine phosphatase-2 (SHP-2), the
ras/raf/MAPK pathway, signal transducer and activator of transcription
factor-3 STAT-3) (Wang S, Zhang W 2016), and PI3K/Akt (Zegeye et al.,
2018), which are translocated into the nucleus to activate target genes
(Figure 1).
IL-6 has been closely associated with SARS-CoV-2 induced cytokine storm.
IL-6 is one of the key cytokines that is frequently reported to be
increased in COVID-19 patients with hypercytokinemia (Kaman, Azmy,
Chichra, Britto-Leon & Price, 2021). The level of IL-6 is valuable as a
prognostic parameter for the disease severity in COVID-19 patients (Liu
et al., 2020). Increasing IL-6 concentrations are associated with the
requirement of ventilatory support, the progression of ARDS, and the
risk of death (Herold et al., 2020; Wu et al., 2020a). Although a
positive correlation between IL-6 and CRP exists in COVID-19 patients,
IL-6 appears to be a better predictor for the disease progression, since
IL-6, not CRP, levels were significantly lower in survivors than in
non-survivors of all age groups of COVID-19 patients, suggesting that
IL-6 is predictive of in-hospital mortality after SARS-CoV-2 infection
(Santa Cruz et al., 2021; Zhang et al., 2020).
Since IL-6 functions through its receptor and the monoclonal antibody
against IL-6R has been developed to prevent the activation of IL-6R by
IL-6. Tocilizumab is a monoclonal antibody against IL-6R that has been
approved by the US FDA for the treatment of cytokine release syndrome.
It is also rational to expect tocilizumab to be capable of attenuating
the cytokine storm induced by SARS-CoV-2 (Pelaia, Calabrese, Garofalo,
Bruni, Vatrella & Pelaia, 2021).
Primary data using tocilizumab demonstrated some benefits for critical
COVID-19 patients. Tocilizumab can rapidly resolve the symptoms. In
severe COVID-19 patients, fever returned to normal on the first day
after tocilizumab administration; other symptoms were improved
remarkably within a few days: 75.0% of patients reduced their
requirement of oxygen intake within 5 d; and the percentage of
lymphocytes in peripheral blood returned to normal in 52.6% of patients
on the fifth day after treatment (Xu et al., 2020).
In severe to critical COVID-19 disease with hypercytokinemia in ICU,
tocilizumab significantly reduced inflammatory response illustrated by
the decrease in CRP, decreased the requirement of respiratory support,
and lowered the mortality (Nasa et al., 2020). The cases with
unfavorable outcomes after tocilizumab treatment were linked to the
failure in reducing the level of CRP (Luo, Liu, Qiu, Liu, Liu & Li,
2020). In addition, since IL-6 is the main inducer of CRP production in
the liver during the acute phase response (Sproston, El Mohtadi, Slevin,
Gilmore & Ashworth, 2018), tocilizumab seemed to be more effective in
patients with markedly elevated CRP (> 200 mg/L) . Systemic
review of the online data suggests that addition of tocilizumab to the
standard of care might reduce mortality in severe COVID-19; however, the
inconsistency in the effectiveness exists among patients with reduced
severity (Boregowda, Perisetti, Nanjappa, Gajendran, Kutti Sridharan &
Goyal, 2020; Gorgolas Hernandez-Mora et al., 2021).
The severity of COVID-19 is an important parameter that affects the
effectiveness of tocilizumab, since tocilizumab given to severe, not
critical (requirement of intubation or ICU admission), SARS-CoV-2
pneumonia patients increased the requirement of intubation and elevated
the mortality. In contrast, in patients with COVID-19 pneumonia and
life-threatening acute respiratory distress syndrome (ARDS) requiring
ventilatory support, intravenous administration of tocilizumab
significantly improve the patients’ respiratory conditions and
downregulate the inflammatory markers (Conrozier et al., 2020; Toniati
et al., 2020). However, two phase III clinical trials include an earlier
one by Roche (Roche, 2020) and a recent report (Rosas et al., 2021), the
use of tocilizumab in hospitalized patients with severe COVID-19
pneumonia did not result in significantly better clinical status or
lower mortality.
In conclusion, the effectiveness of tocilizumab might be subjected to
various factors, such as the severity of the disease and the
inflammatory status. The value of tocilizumab in the treatment of
COVID-19 should be further evaluated. One side effect of tocilizumab is
that its administration in COVID-19 patients significantly increased
IL-6 levels (Antwi-Amoabeng, Kanji, Ford, Beutler, Riddle & Siddiqui,
2020). Tocilizumab only blocks IL-6R without effects on the production
of IL-6. Blockade of IL-6R might reduce the IL-6 consumption that leads
to an increase in IL-6 (Nishimoto, Terao, Mima, Nakahara, Takagi &
Kakehi, 2008). The concern is whether higher IL-6 levels after
tocilizumab treatment in COVID-19 patients would have adverse effects or
exacerbate the CNS inflammation due to impermeability of BBB to
tocilizumab (Zhang et al., 2020).
Since it is the trans IL-6 pathway that has been associated with
inflammation, the specific antagonists for this pathway might increase
the efficacy and reduce the side effects. The development of regulators
of trans-IL-6 signaling pathway may hold better promise for the
treatment of COVID-19.