Abstract
Upon repeated exposure to endotoxin or lipopolysaccharide (LPS), myeloid cells enter a refractory state called endotoxin tolerance as a homeostatic mechanism. In innate immune cells, LPS is recognized by co-receptors Toll-like receptor 4 (TLR4) and CD-14 to initiate an inflammatory response for subsequent cytokine production. One such cytokine, interleukin (IL)-27, is produced by myeloid cells in response to bacterial infection. In monocytes, IL-27 has proinflammatory functions such as up-regulating TLR4 expression for enhanced LPS-mediated cytokine production; alternatively, IL-27 induces inhibitory functions in activated macrophages. This study investigated the effects of IL-27 on the induction of endotoxin tolerance in models of human monocytes compared with macrophages. Our data demonstrate that IL-27 inhibits endotoxin tolerance by up-regulating cell surface TLR4 expression and soluble CD14 production to mediate stability of the surface LPS-TLR4-CD14 complex in THP-1 cells. In contrast, elevated basal expression of membrane-bound CD14 in phorbol 12-myristate 13-acetate (PMA)-THP-1 cells, primary monocytes, and primary macrophages may promote CD14-mediated endocytosis and be responsible for the preservation of an endotoxin-tolerized state in the presence of IL-27. Overall, the efficacy of IL-27 in inhibiting endotoxin tolerance in human THP-1 monocytes and PMA-THP-1 macrophages is affected by membrane-bound and soluble CD14 expression.
Highlights
Upon repeated exposure to endotoxin or lipopolysaccharide (LPS), myeloid cells enter a refractory state called endotoxin tolerance as a homeostatic mechanism
We investigated the effects of IL-27 on Toll-like receptor 4 (TLR4)/CD14 receptor expression, LPS binding, and signal transduction in THP-1 monocytes compared with phorbol 12-myristate 13-acetate (PMA)–THP-1 macrophages as well as downstream LPSmediated cytokine production
This study focused on the effects of IL-27 on LPS-mediated endotoxin tolerance and found that IL-27 differentially inhibited the induction of endotoxin tolerance in human myeloid cells dependent on both membrane and soluble CD14 expression
Summary
LPS is recognized by co-receptors Toll-like receptor 4 (TLR4) and CD-14 to initiate an inflammatory response for subsequent cytokine production. We investigated the effects of IL-27 on TLR4/CD14 receptor expression, LPS binding, and signal transduction in THP-1 monocytes compared with PMA–THP-1 macrophages as well as downstream LPSmediated cytokine production. The heightened effects of IL-27 on the induction of endotoxin tolerance in THP-1 cells compared with PMA–THP-1 cells may depend on CD14-mediated mechanisms for subsequent TLR4 signal transduction in the endosome. Understanding the mechanisms used by IL-27 to alter LPS responsiveness may reveal novel targets for prevention, diagnosis, or treatment of inflammatory illnesses affiliated with endotoxin tolerance, such as septic shock
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