Signaling Networks Responsible for the Dynamic Modulation of IL-12 in Response to Varying Dosages of LPS in MacrophagesJournal: Journal of Vaccine & Immunotechnology (Vol.1, No. 1)
Publication Date: 2014-12-30
Authors : Matthew C. Morris; Julia L. Button; Brianna K. Swartwout; Liwu Li;
Page : 1-6
Keywords : ;
The innate immune response to lipopolysaccharide (LPS) has many possible outcomes depending on the dose, from acute endotoxic shock to broad immunomodulation. High doses (>10 ng/mL) evoke both pro- and anti-inflammatory mediators, while super-low doses (<1 ng/mL) result in preferential induction of pro-inflammatory genes. The mechanisms governing the switch between a preferentially proinflammatory or a balanced, resolving response are poorly understood. We show that in murine macrophages, the pro-inflammatory cytokine interleukin 12 (IL-12) is induced most robustly by intermediate LPS doses (1-10 ng/mL), while higher doses evoke a diminishing response. In the absence of the suppressive Toll-like receptor 4 signaling cascade members Lyn and IRAK-M, macrophages sustain robust IL-12 production in response to high doses of LPS. The transcription factor cAMP response element-binding protein (CREB) appears to play an important role in the regulation of the inflammatory response to LPS, with Lyn and IRAK-M deficient macrophages failing to activate CREB effectively in response to LPS. On the other hand, co-stimulation of these cells with LPS and the CREB agonist adenosine suppresses proinflammatory responses to LPS in wild-type cells, but does not robustly suppress IL-12 production in either Lyn- or IRAK-M-deficient cells. Our study reveals potential mechanisms for the dynamic modulation of innate responses by varying dosages of LPS.
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