Novel cytokines in innate immunity: IL-27 and IL-30 enhance responsiveness to gram-negative bacterial components in human myeloid cells
In response to microbial stimuli, innate myeloid cells are potent producers of cytokines that function to mediate inflammation. This thesis investigates two related cytokines, IL-27 and IL-30, to identify novel proinflammatory mechanisms to improve treatments for bacterial infections. IL-27 is comprised of IL-27p28 and EBI3 subunits; the IL-27p28 subunit, also named IL-30, can also signal independently of EBI3. To date, most studies on IL-27 have focused on its role in CD4+ T cell differentiation. IL-30 has been recognized as an antagonist of IL-6, IL-11, and IL-27 in CD4+ T cells. In primary monocytes, IL-27 promotes proinflammatory cytokine production and TLR4 expression in monocytes for a potent inflammatory response to bacterial endotoxin, LPS. Barring these studies, functions of IL-27 and IL-30 in human myeloid cells have not been well described, and therefore are the focus of this thesis. Specifically, this thesis compares IL-27 and IL-30 signaling in human monocytes and explores novel proinflammatory effects of IL-27 and IL-30 on cytokine production in response to either Gram-negative bacteria or bacterial components in myeloid cells. The effects of IL-27 are explored in Salmonella enterica infection, NLRP3 inflammasome activation, and induction of endotoxin (LPS) tolerance in human monocytes and macrophages, while the effects of IL-30 are defined in human monocytes. IL-27 and IL-30 induce IP-10 production in human monocytes in a STAT-dependent manner. Furthermore, pre-treatment with IL-6 interferes with IL-27 and IL-30 functions in human monocytes. Similarly to TLR4, IL-27 treatment also enhances TLR5 expression in human monocytes and macrophages, inducing cytokine production in response to TLR agonists LPS and flagellin or S. enterica infection. IL-27 also increases LPS/ATP-mediated NLRP3 inflammasome activation and IL-1β production in human monocytes via upregulated TLR4 and P2X7 expression. Comparing human THP-1 monocytes and PMA-differentiated THP-1 macrophages, CD14 expression plays a role in LPS and IL-27 responsiveness, whereby IL-27-mediated inhibition of LPS tolerance is greater in CD14low THP-1 monocytes compared to CD14high PMA-differentiated THP-1 macrophages. Overall, this thesis demonstrates novel proinflammatory roles for IL-27 and its subunit IL-30 in innate immune responses and may serve as novel adjuvant candidates for vaccine design against Gram-negative bacterial infections.
URI for this recordhttp://hdl.handle.net/1974/24492
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