Pro- or anti-inflammatory properties of cytokines in COVID-19: which offer better protection against disease

Pro- or anti-inflammatory properties of cytokines in COVID-19: which offer better protection against disease
I read the article by Al-Mquter et al. that compared circulating levels of 3 cytokines(IL-6, IL-25 and IL-35) amongst healthy controls(HC) and patients with COVID-19. They reported a significant increase in the serum concentration of these cytokines in patients versus HC(1). Their results confirmed again that assessment of cytokine profiles could be used as COVID-19 markers and may also provide practical implications for disease treatment. Nonetheless, understanding the role of cytokines in COVID-19 is complicated because of the complex nature of cytokine networks and the pathogenesis of COVID-19(2). IL-6 is one of the first cytokines produced during COVID-19 and increasing evidence suggests that its alteration may be associated with disease outcome.
IL-6 is a pleotropic cytokine and has both pro- and anti- inflammatory effects. Therefore, it appears to operate in protective or pathological immunity to COVID-19. IL-6 can promote immune processes associated with resistance to different pathogens including COVID-19. It contributes to host defense via different pathways, including the stimulation of acute phase responses and hematopoiesis. Nonetheless, dysregulated and persistent synthesis of IL-6 can be resulted to the onset and development of pathological conditions. These different effector functions may be associated with different concentration of IL-6 that may result from different signaling pathwaysIL-6 signaling includes at least three distinct pathways: cis-signalling; trans-signalling and trans-presentation. It seems that IL-6 trans-signalling and trans-presentation are probably responsible for severe progressive COVID-19. These signaling pathways can trigger diffuse inflammation at various levels. Conversely, IL-6 cis-signalling mediates negative feedback mechanisms on proinflammatory cytokines, including suppression of their production, stimulation of their decoy receptors, and inhibition the maturation of Th17 cells. Circulatory IL-6 in COVID-19 patients reaches the peak level at advanced stages around two weeks of disease. Elevated IL-6 (e.g., > 100-120 pg/mL) levels in critical COVID-19 may reflect augmented IL-6 cis-signalling in an attempt to exert homeostatic functions, although there is no general consensus on this issue(3).