21 research outputs found
The beneficial effect of hydroxyapatite lasts: A randomized radiostereometric trial comparing hydroxyapatite-coated, uncoated, and cemented tibial components for up to 16 years
Analysis and Stochastic
Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells
The innate immune system, acting as the first line of host defense, senses
and adapts to foreign challenges through complex intracellular and
intercellular signaling networks. Endotoxin tolerance and priming elicited by
macrophages are classic examples of the complex adaptation of innate immune
cells. Upon repetitive exposures to different doses of bacterial endotoxin
(lipopolysaccharide) or other stimulants, macrophages show either suppressed or
augmented inflammatory responses compared to a single exposure to the
stimulant. Endotoxin tolerance and priming are critically involved in both
immune homeostasis and the pathogenesis of diverse inflammatory diseases.
However, the underlying molecular mechanisms are not well understood. By means
of a computational search through the parameter space of a coarse-grained
three-node network with a two-stage Metropolis sampling approach, we enumerated
all the network topologies that can generate priming or tolerance. We
discovered three major mechanisms for priming (pathway synergy, suppressor
deactivation, activator induction) and one for tolerance (inhibitor
persistence). These results not only explain existing experimental
observations, but also reveal intriguing test scenarios for future experimental
studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte
LPS and Taxol Activate Lyn Kinase Autophosphorylation in Lpsn, but Not in Lpsd, Macrophages
Strong inflammatory cytokine response in male and strong anti-inflammatory response in female kidney transplant recipients with urinary tract infection
Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase
Intestinal alkaline phosphatase (IAP) is a small intestinal brush border enzyme that has been shown to function as a gut mucosal defense factor, but its precise mechanism of action remains unclear. We investigated the effects of IAP on specific bacteria and bacterial components to determine its molecular targets. Purulent fluid from a cecal ligation and puncture model, specific live and heat-killed bacteria (Escherichia coli, Salmonella typhimurium, and Listeria monocytogenes), and a variety of proinflammatory ligands (LPS, CpG DNA, Pam-3-Cys, flagellin, and TNF) were incubated with or without calf IAP (cIAP). Phosphate release was determined by using a malachite green assay. The various fluids were applied to target cells (THP-1, parent HT-29, and IAP-expressing HT-29 cells) and IL-8 secretion measured by ELISA. cIAP inhibited IL-8 induction by purulent fluid in THP-1 cells by >35% (P < 0.005). HT29-IAP cells had a reduced IL-8 response specifically to gram-negative bacteria; >90% reduction compared with parent cells (P < 0.005). cIAP had no effect on live bacteria but attenuated IL-8 induction by heat-killed bacteria by >40% (P < 0.005). cIAP exposure to LPS and CpG DNA caused phosphate release and reduced IL-8 in cell culture by >50% (P < 0.005). Flagellin exposure to cIAP also resulted in reduced IL-8 secretion by >40% (P < 0.005). In contrast, cIAP had no effect on TNF or Pam-3-Cys. The mechanism of IAP action appears to be through dephosphorylation of specific bacterial components, including LPS, CpG DNA, and flagellin, and not on live bacteria themselves. IAP likely targets these bacterially derived molecules in its role as a gut mucosal defense factor