Interleukin is a family of cytokines with bidirectional immune-modulatory effects, mainly involved in the differentiation and activation of immune cells. IL-12 family, as inflammatory factors, includes IL-12, IL-23, IL-27, IL-35, and IL-39. IL-12 is a key immune-regulatory cytokine, which bridges nonspecific innate resistance and antigen-specific adaptive immunity [
49]. IL-12 plays a crucial role in type 1 immunity, which induces many cytokines and inflammatory responses. IL-12 has a protective effect and increases the resistance to infection in herpes simplex virus type 1(HSV-1)-thermally injured mice. IL-12 could down-regulate PD-1 and increase CD8 functionality for immunity in persistent HBV infections [
50]. IL-23 is a pro-inflammatory cytokine as well as IL-12, which promotes the proliferation of T cells and memory T cells and the production of IFN-
γ. IL-23 enhances IFN-α responsiveness to promote HCV eradication. IL-23 promotes host resistance vaccinia virus infection via the IL-23/IL-17 axis. IL-23 produced by myeloid dendritic cells induces SOCS1 expression and causes T cell dysfunction during HIV infection [
51]. IL-27 is secreted by antigen-presenting cells such as macrophages and dendritic cells (DCs), which has a dual role in immune regulation [
52]. As an anti-inflammatory role, IL-27 could induce IL-10 producing Tr1 cells capable of inhibiting Th1 and Th17 type responses, but also as a pro-inflammatory cytokine to break down CD4
+ Tregs or by activating Th1 differentiation [
53]. IL-27 has broad anti-viral effects, such as HIV-1, HCV, herpes simplex virus type 1 (HSV-1), and HBV, but the mechanism differs. IL-27 could prevent macrophages from HIV-1 infection by down-regulating spectrin β none-erythrocyte 1 (SPTBN1). IL-27 is capable to suppress HCV replication by inducing the activation of STAT-1 and it can also control HSV-1 infection via the up-regulation of STAT-1, IL-6, and IP-10 and MIG [
54]. IL-35, a newly identified member of the IL-12 family, suppresses immunity by regulatory T and B cells and plays an important role in the immune tolerance period of viral infection. IL-35 induces immune-tolerance through suppressing pro-inflammatory cytokine expression during chronic HBV infection [
55]. IL-35 contributes to prevent HCV-induced liver damage via reducing inflammatory responses, while play a contradictory role in persistent HCV infection by the inhibition of antiviral immune activity. IL-35 is the high expression in peripheral blood mononuclear cells and throat swabs of patients with seasonal IAV, which inhibits IAV RNA replication and viral protein synthesis by induction of type I and III IFN [
56]. Overall, IL-35 plays a critical role in inflammatory and autoimmune diseases, but the functions of IL-35 in antiviral infections are not yet well understood. IL-15 is critical for the development and function of natural killer (NK), NKT, and memory CD8
+ T cells. IL-15 has innate antiviral activity and is an activator of NK cell-mediated antiviral defense [
57]. IL-15 could enhance the killing ability of NK cells while contributing to the synthesis and secretion of IFN. Therefore, IL-15 potentially stimulates NK cells from HIV-positive donors and improves NK cells’ antiviral effects to clear HIV-1-infected cells. IL-15 efficiently enhances the survival and effector function of HIV-specific CD8
+ T cells, which may improve their activity to control HIV [
58]. IL-15 is up-regulated during primary human immunodeficiency virus (HIV) infection, which renders primary human CD4
+ cells more susceptible to HIV. IL-15 and IFN-γ restraints HCV replication via the ERK pathway [
59]. Synergistic effects of IL-15 and IFN-α significantly enhance the CD8
+ T cell response in a state of immune hypo-responsiveness. IL-22 is a member of the IL-10 family of cytokines. It has been documented that IL-22 has a crucial role in many virus infections, including HBV, rotavirus, HIV, influenza virus, dengue virus, and HSV-2 [
60]. IL-22 induces the proliferation of liver stem/progenitor cells via activating STAT3 and reduces pathology in mice and patients with chronic HBV infection. IL-22 could enhance the expression of the interferon-stimulated gene (ISG) and limit rotavirus replication by cooperating with IFN-λ [
61]. After the influenza virus infection, IL-22 promotes epithelial cell regeneration, while prevents lung inflammation and secondary bacterial infection. IL-22 could reduce the secretion of pro-inflammatory cytokines and the accumulation of neutrophil to restrict dengue virus-induced hepatic damage and inflammation [
62]. Studies have indicated that IL-22 has the ability to antiviral by the activation of the JAK/STAT signaling pathway [
63].