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).