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

Abstract

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 be inhibited by activation of TLR7 in monocytes and macrophages. Altogether, this work identifies novel functions of IL-27 in modulating innate immune responsiveness and provides insight into the potential mechanisms behind the anti-microbial promoting properties of this cytokine.