IL-27 bridges innate and adaptive immunity by modulating cytokine production from myeloid cells and regulating Th cell differentiation. During bacterial infection, TLR4 triggering by LPS induces IL-27 production by monocytes and macrophages. We have previously shown that IL-27 can prime monocytes for LPS responsiveness by enhancing TLR4 expression and intracellular signaling. If unregulated, this could result in damaging inflammation, whereas on the other hand, this may also provide greater responses by inflammatory processes induced in response to bacterial pathogens. A key process in fine-tuning inflammatory responses is activation of the inflammasome, which ultimately results in IL-1β production. Herein, we investigated the molecular mechanisms by which IL-27 modulates LPS-induced IL-1β secretion in monocytes and macrophages. We found that when delivered simultaneously with LPS, IL-27 augments activation of caspase-1 and subsequent release of IL-1β. Furthermore, we determined that IL-27 primes cells for enhanced IL-1β production by up-regulating surface expression of TLR4 and P2X purinoceptor 7 (P2X7) for enhanced LPS and ATP signaling, respectively. These findings provide new evidence that IL-27 plays an important role in the proinflammatory capacity of monocytes and macrophages via enhancing IL-1β secretion levels triggered by dual LPS-ATP stimulation.
The interleukin (IL)-12 family cytokine, IL-27 has been implicated in the pathogenesis of many autoimmune inflammatory disorders, including rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, and ulcerative colitis. Discovered in 2002, IL-27 has been primarily described as an anti-inflammatory cytokine with regulatory roles in multiple sclerosis and experimental autoimmune encephalitis. However, recent studies have demonstrated a pro-inflammatory function of IL-27 in both the adaptive and innate immune responses. This review will focus on the proinflammatory nature of IL-27 in chronic inflammatory skin disease and inflammatory bowel disease.
The inflammasome is a multimeric protein complex required for interleukin (IL)-1β production. Upon lipopolysaccharide (LPS) triggering of toll-like receptor (TLR)-4 and subsequent ATP signaling, the NOD-like receptor containing-pyrin domain 3 (NLRP3) inflammasome is activated to cleave pro-caspase-1 into caspase-1, allowing the secretion of IL-1β. IL-1β is known to function with IL-23 in the regulation of IL-17-producing CD4(+) T cells, Th17 cells, in adaptive immunity. Recently, studies have shown that IL-1β and IL-23 together activate IL-17-producing innate lymphoid cells, demonstrating that the pair may exhibit additional effects on cell differentiation. Using an in vitro model of bacterial infection, LPS treatment of human monocytic cells, we investigated the molecular mechanisms involved in the co-expression of IL-1β and IL-23. We found that IL-1β is partially required for optimal LPS-induced IL-23 production. We also found that IL-23 production was partially dependent on ATP signaling via the P2X7 receptor, whereas IL-1β production required this signaling. Furthermore, we identified a novel role for cathepsin B activity in IL-23 production. Taken together, this study identifies differential requirements for the co-expression of IL-1β and IL-23. Due to their similar roles in Th17 differentiation, characterization of the regulatory mechanisms for LPS-induced IL-1β and IL-23 may reveal novel information into the pathology of the inflammatory response particularly during bacterial infection.
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