The Role of Interleukin 6 During Viral Infections

Abstract

Our recently published research on the characterization of vesicular stomatitis virus (VSV) pathogenesis in swine, identified a systemic upregulation of interleukin 6 (IL-6) during the acute phase of infection (Velazquez-Salinas et al., 2018). This upregulation was observed during infection with a highly virulent VSV strain, suggesting a potential association between IL-6 levels and virus virulence in pigs. In this opinion note we would like to explore in more detail the biological functions of IL-6 in different virus models, and present our perspective regarding the debatable role of IL-6 during viral infections. While several studies show the essential role of IL-6 to mount a proper immune response during some viral infections, others link this cytokine with exacerbation of viral disease. These latter findings lend support to the hypothesis that upregulation of IL-6 during certain viral infections may promote virus survival and/or exacerbation of clinical disease. IL-6 is a pleotropic cytokine produced in response to tissue damage and infections (Tanaka et al., 2014). Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine (Mauer et al., 2015). After targeting its specific receptor, IL-6 starts a cascade of signaling events mainly associated with the JAK/STAT3 activation pathway (Wang et al., 2013) promoting the transcription of multiple downstream genes associated with cellular signaling processes, including cytokines, receptors, adaptor proteins, and protein kinases (Pim-1, LDL-receptor, GADD45 beta, SOCS1, MAP3K8, SOCS3, GLUT3, HB-EGF, ICAM1, Mx1, PTP4A3, SGK, Pim-2, RHOBTB3, cAMP-GEFII, PDGF-receptor alpha, MLCK). It also controls the production of proteins implicated in regulation of gene expression (Blimp1, id-2H, MAFF, TTP, C/EBP-beta, SRY, TCF8, c-jun, junB, Bcl-3, Bcl-5, DEC1, Nmi, Stat1, eIF5, OBF-1, Oct-2, Stat3; Brocke-Heidrich et al., 2004). The number of genes regulated by IL-6 activity may explain the pleotropic nature of this interleukin. Accordingly, the biological consequences of IL-6 production have been associated with both pro- and anti-inflammatory effects (Scheller et al., 2011), highlighting IL-6's pivotal role in the activation and regulation of the immune response. Biological activities affected by production of IL-6 include: control of the differentiation of monocytes into macrophages by regulating the expression of macrophage colony-stimulating factor (Chomarat et al., 2000), increasing B-cell IgG production by regulating the expression of IL-21 (Yang et al., 2016), negative regulation of dendritic cell maturation by activation of the STAT3 signaling pathway (Park et al., 2004), as well as the promotion of the Th2 response by inhibiting Th1 polarization (Diehl and Rincon, 2002). Two different mechanisms have been described to promote the inhibition of Th1 polarization by IL-6: (1) IL-6 stimulates CD4 T cells to secrete IL-4 and direct the response to Th2, and (2) IL-6 affects the secretion of IFNγ by CD4 T cells, an essential interferon to promote Th1 polarization. A similar effect is produced in Th1 cells, where inhibition of IFNγ secretion in these cells affects CD8 T cell activation (Dienz and Rincon, 2009; Green et al., 2013). Moreover, in combination with the transforming growing factor beta, IL-6 induces the differentiation of naïve CD4 into Th17 cells, which are important for the defense against pathogens at mucosal sites (Guglani and Khader, 2010). Also, IL-6 synergic interactions with IL-7 and IL-15 induce the differentiation and cytolytic capacity of CD8 T cells (Cox et al., 2013). Importantly, IL-6 is a potent pyrogenic cytokine, and has an essential role organizing lymphocyte trafficking to lymphoid organs during febrile events (Evans et al., 2015). In addition to its roles modulating the host immune response, IL-6 has been implicated in the progression of several virus infectious. IL-6 is considered one of the most important cytokines during an infection, along with interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-a; Dienz and Rincon, 2009). Direct evidence supporting the importance of IL-6 during viral infections has been gathered in experimental infections using IL-6-deficient mice. Using this model, IL-6 has been shown to be essential for survival of mice infected with influenza virus by promoting optimal regulation of the T-cell response, inflammatory resolution, tissue remodeling promoting lung repair, migration and phagocytic activities of macrophages, preventing viral-induced apoptosis in lung epithelial cells, and regulation of IgG isotype switching (Lauder et al., 2013; Yang et al., 2017). Other reports have also emphasized the importance of IL-6 during virus infections. Disruption of the IL-6 gene in mice infected with vaccinia virus impaired the immune response by reducing the activity of specific cytotoxic T-cells, while murine infection with VSV impaired the production of specific IgG antibodies (Kopf et al., 1994). Additional evidence of IL-6's function during a virus infection was observed during lymphocyte choriomeningitis virus infection of mice where IL-6 and/or IL-6R activity was blocked using specific monoclonal antibodies. In this model, T helper and B-cell responses were reduced during the late stages of infection, negatively affecting viral clearance (Harker et al., 2011). Genetically engineered rabies virus carrying the IL-6 gene in its genomic backbone has been used as an alternative model of experimentation to assess the relevance of IL-6 during viral infections (Luo et al., 2018). Normal mice infected with this virus showed a higher resistance to the viral infection compared with mice infected with the parental virus. Animals infected with the engineered virus had an increased blood-brain barrier permeability with a higher number of...