5.3. Janus-associated kinase (JAK)
The JAK family is one of ten recognized families of non-receptor
tyrosine kinases. Mammalian members of Jaks family are Jak1, Jak2, Jak3
and Tyrosine kinase 2 (Tyk2). JAK-STAT-pathway mediates the downstream
signals of multiple cytokines and inhibitors of JAK/STAT have been used
in the treatment of inflammatory diseases (El Jammal, Gerfaud-Valentin,
Seve & Jamilloux, 2020; Jamilloux, El Jammal, Vuitton,
Gerfaud-Valentin, Kerever & Seve, 2019). JAK associates with cytokine
receptors to mediate cytokines induced signaling pathways. JAK1 and JAK2
regulate cell signaling pathways of cytokines, such as IL-2, IL-4, IL-7,
IL-9, and IL-15, that share common γ chain (γc) as receptor subunit
(Moradian et al., 2020; Pesu, Laurence, Kishore, Zwillich, Chan &
O’Shea, 2008). JAK1 also regulate cell signaling downstream of IL-6,
which activate their receptor to initiate the dimerization of receptor
subunit gp130 (Barkhausen et al., 2011). JAK2 activation is essential
for the signaling transduction of erythropoietin and other growth
factors (Maiese, Chong, Shang & Wang, 2012).
Since the multiple cytokines are involved in SARS-CoV-2 induced cytokine
storm, JAK inhibitors have been therapeutically used in COVID-19
patients (Seif et al., 2020). Ruxolitinib is a potent and selective
inhibitor of JAK1/2 with some levels of inhibitory effects on TYK2 and
JAK3. COVID-19 patients received ruxolitinib plus standard-of-care
treatment showed a faster clinical improvement on CT images with
decreased levels of cytokines including IL-6, nerve growth factor β,
IL-12, migration inhibitory factor, MIP-1α, MIP-1β, and VEGF, although
it was not associated with significantly accelerated clinical
improvement in severe cases (Cao et al., 2020b). Treatment with
ruxolitinib in COVID-19 patients with severe systemic hyperinflammation,
who suffered from progression to ARDS and multiorgan failure,
significantly reduced the inflammatory score with sustained clinical
improvement (La Rosee & La Rosee, 2020). For an example, ruxolitinib,
given to a 65-year-old Asian woman with COVID-19-induced ARDS, not only
potently reduced ARDS-associated inflammatory blood cytokine levels such
as IL-6 and the acute phase protein ferritin, but also associated with a
rapid respiratory and cardiac improvement and clinical stabilization
(Neubauer et al., 2020).
Baricitinib is an oral JAK inhibitor. Clinical studies have demonstrated
the ability of baricitinib to reduce the viral titers and decrease IL-6
level with resolution of fever and cough symptoms in COVID-19 patients
(Richardson, Ottaviani, Prelle, Stebbing, Casalini & Corbellino, 2020;
Stebbing et al., 2021). In COVID-19 pneumonia, baricitinib treatment
reduced the serum levels of IL-6, IL-1β, and TNF-α, promoted the
recovery of circulating T and B cell frequencies, increased antibody
production against the SARS-CoV-2 S-protein, and reduced patients’ need
for oxygen therapy (Bronte et al., 2020). In moderate to severe
SARS-CoV-2 pneumonia, baricitinib has add-on effect when combined with
corticosteroids in improving pulmonary function (Rodriguez-Garcia,
Sanchez-Nievas, Arevalo-Serrano, Garcia-Gomez, Jimenez-Vizuete &
Martinez-Alfaro, 2021). Baricitinib exerts both anti-inflammatory and
anti-viral activities effects and one additional advantage is its
ability to cross BBB into the CNS (Richardson, Ottaviani, Prelle,
Stebbing, Casalini & Corbellino, 2020).