Novel Functions of IL-27 in Innate Immunity: Characterization of IL-27-induced Inflammatory Responses in Human Monocytes and Impact of HIV Infection on IL-27 Expression and Function
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Interleukins, cytokines secreted by leukocytes, are predominant messengers modulating immune responses. Interleukin-27 (IL-27), a key immunomodulatory cytokine, functions to induce both pro- and anti-inflammatory effects in various immune cells. IL-27 is a heterodimeric cytokine, composed of IL-27p28 and Epstein-Bar virus induced gene 3 (EBI3) subunits, and binds to a receptor composed of IL-27Rα (WSX-1) and gp130. Initial studies focused on describing IL-27 functions in skewing T helper cell development to a Th1 response, with few reports on functions in monocytes. Thus, in this thesis, I aimed to characterize novel functions of IL-27 in innate immune responses of monocytes. I initially established that IL-27 induced a pro-inflammatory cytokine profile (IL-6, IP-10, MIP-1α, MIP-1β, and TNF-α) mediated via STAT1/3 and NF-κB signaling pathways. Further investigation led to the discovery that IL-27 could enhance LPS responses via upregulation of TLR4 expression and NF-κB signaling. Together, these studies described novel signaling mechanisms (NF-κB and JAK/STAT crosstalk) and gene targets (cytokines and TLR4) of IL-27 that drive inflammatory responses. In continuing the quest for novel IL-27 functions in innate immunity, I reported IL-27 can upregulate expression of the IFN-responsive, antiviral protein called BST-2. My results showing IL-27-induced expression of BST-2 mRNA and cell surface protein were supported by previous studies reporting IL-27-induced expression of other antiviral molecules. Furthermore, previous studies showed IL-27 could inhibit HIV replication via antiviral gene induction, pointing to potential for IL-27 immunotherapies. In light of the posited role for IL-27 in therapeutics, it became inherently critical to describe how IL-27 functions in the setting of HIV infection. Thus, in my final thesis chapters, I described the effect of HIV infection on IL-27 expression and functions, addressing a substantial void in literature. Interestingly, a trend of decreased IL-27 expression and significant impairment of IL-27-induced gene expression was observed in HIV infection. Therefore, decreased circulating IL-27 and decreased IL-27 responsiveness may collectively dysregulate IL-27 function in HIV. This thesis describes novel, IL-27-driven, proinflammatory responses, and highlights impairment of IL-27 function in HIV infection. This work bridged a gap in knowledge of IL-27 functions in monocytes and highlighted multifaceted mechanisms underlying immunoregulation by IL-27.