Interleukin-27 Modulates Monocyte and Macrophage Toll-Like Receptor Responses to Bacterial and Viral Components

Interleukin (IL)-27 is a heterodimeric cytokine with pleiotropic functions across both innate and adaptive immunity. Composed of subunits IL-27p28 and EBI3, IL-27 signals via a heterodimeric receptor of gp130 and WSX-1 to activate STAT1 and STAT3 homo- and heterodimers. As a cytokine produced in response to Toll-like receptor (TLR) signaling, IL-27 plays a role in modulating immune cell function during infection. TLRs are a class of pattern recognition receptors involved in the detection of pathogen associated molecular patterns (PAMPs) and corresponding induction of proinflammatory immune responses. Although IL-27 was originally identified as a mediator of helper T cell function, new functions of IL-27 on innate immune cells have come to light on myeloid cells, including enhancing antigen presentation as well as anti-microbial properties. Several anti-viral functions of IL-27 have been identified and it has been established that IL-27 can amplify responsiveness to lipopolysaccharide (LPS). The specific role of IL-27 during these anti-microbial responses is still largely unknown. While these new properties of IL-27 have been identified, how IL-27 modulates innate immune receptors such as TLRs that are involved in microbial recognition has not been investigated. In this thesis, how IL-27 impacts the expression and function of anti-bacterial TLRs, TLR4 and TLR5 and anti-viral endosomal TLRs, TLR7 and TLR8, is investigated using a model of human monocytes and macrophages. Upon stimulation with IL-27, monocytes and macrophages displayed enhanced TLR4, TLR5 and TLR7 expression, but expression of TLR8 was unaffected. TLR4 and TLR5 signaling, and TLR4-mediated cytokine production, was amplified by IL-27 in response to ligand stimulation. However, dissimilar to the anti-bacterial TLRs, the enhanced TLR7 expression did not result in amplified cytokines responses. Instead, TLR8 activity was amplified by IL-27 stimulation, even though its expression remained constant. Additionally, inhibition of TLR8 activity was shown to ...