**3.2 The up regulation of IL-6 in RNA virus infection**

In common, pathogen-associated molecular patterns (PAMPs) recognized by pathogen recognition receptors (PRRs) in RNA virus infected lesions. The damageassociated molecular patterns (DAMPs) released from damaged cells in non-infectious inflammation will provoke IL-6 synthesis in many cells such as immune-competent cells, mesenchymal cells, fibroblasts, endothelial cells, and epithelial cells [10, 11]. The IL-6 initiates warning signals to the entire body, and many experiments have shown that serum IL-6 levels are elevated in patients RNA virus infection. Some studies in Hepatitis B virus infection showed that IL-6 is also a good marker for HBV-related disease progression [12]. The levels of IL-6 are significantly higher in chronic hepatitis B (CHB) patients than in healthy individuals [13]. The IL-6 is also significantly higher in patients with advanced liver disease (LC or HCC) compared to the CHB groups [14].

The IL-6 is an important proinflammatory cytokines during RNA virus infection onset, especially, at the mucosal sites. However, the impact of IL-6 on the disease outcome may vary significantly. The IL-6-dependent Th17 activation and differentiation are important for effective neutrophil migration, IL-6 together with IL-15 modulate cytolytic capacity of CD8+ T cells [15]. In this part, IL-6, as a pyrogenic cytokine, contributes to thermostatic regulation that is very important for effective anti-viral response [16].

On the other hand, the upregulation of IL-6 has been implicated in the progression of RNA viral infections. In this part, IL-6 synergizes with IL-1b and TNF to upregulate trypsin expression, trypsin activates matrix metalloproteinases and causes the breakdown of basal membrane and extracellular matrix, that cause increased tissue permeability and edema [17]. The upregulation of IL-6 promotes Th17 cell differentiation and IL-17A secretion, which, in turn, activates the expression of anti-apoptotic molecules, such as Bcl-XL, favoring survival of virus-infected cells in the model of persistent viral infection [18]. In the COVID-19 infection, the increase of IL-17 that mediated by IL-6 promotes the migration of neutrophils whichcontribute to the pathogenesis of ARDS [19, 20].

