ABSTRACT
The Toll family of proteins is central to Drosophila host defense against microbial infection. Maintained throughout evolution, mammalian Toll-like receptors (TLRs) are proteins that participate in innate immunity to bacteria in at least four ways. First, TLRs participate in the recognition of molecular patterns present on microorganisms. Second, TLRs are expressed at the interface with the environment, the site of microbial invasion. Third, activation of TLRs induces expression of co-stimulatory molecules and the release of cytokines that instruct the adaptive immune response. Fourth, activation of TLRs leads to direct antimicrobial effector pathways that can result in elimination of the foreign invader. The recent investigation of TLRs in these areas has provided new insights into mechanisms of innate immunity.
Subject(s)
Drosophila Proteins , Gram-Negative Bacterial Infections/immunology , Gram-Positive Bacterial Infections/immunology , Membrane Glycoproteins/physiology , Receptors, Cell Surface/physiology , Animals , Gram-Negative Bacterial Infections/metabolism , Gram-Positive Bacterial Infections/metabolism , Humans , Immunity, Innate , Toll-Like ReceptorsABSTRACT
The generation of cell-mediated immunity against many infectious pathogens involves the production of interleukin-12 (IL-12), a key signal of the innate immune system. Yet, for many pathogens, the molecules that induce IL-12 production by macrophages and the mechanisms by which they do so remain undefined. Here it is shown that microbial lipoproteins are potent stimulators of IL-12 production by human macrophages, and that induction is mediated by Toll-like receptors (TLRs). Several lipoproteins stimulated TLR-dependent transcription of inducible nitric oxide synthase and the production of nitric oxide, a powerful microbicidal pathway. Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens.
Subject(s)
Antigens, Bacterial/immunology , Drosophila Proteins , Interleukin-12/biosynthesis , Lipoproteins/immunology , Macrophages/immunology , Membrane Glycoproteins/metabolism , Monocytes/immunology , Mycobacterium tuberculosis/immunology , Receptors, Cell Surface/metabolism , Animals , Antigens, Bacterial/chemistry , Antigens, Bacterial/metabolism , Cell Line , Gene Expression Regulation , Humans , Interleukin-12/genetics , Lipopolysaccharides/immunology , Lipoproteins/chemistry , Lipoproteins/metabolism , Macrophages/metabolism , Mice , Monocytes/metabolism , NF-kappa B/biosynthesis , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Promoter Regions, Genetic , Signal Transduction , Toll-Like Receptors , Transcription, Genetic , Transfection , Tumor Cells, CulturedABSTRACT
Plasma parathormone (PTH) and calcium concentrations were measured in 309 specimens collected from 190 newborns during the first 7 days of life. The patient material consisted of 51 preterm, 130 term, and 9 postterm infants, including 22 infants of diabetic mothers (IDM), 38 infants with hypocalcemia, and 25 asphyxiated infants. PTH was detectable, although in low concentrations, in cord blood samples despite the presence of elevated calcium concentrations. Postpartum, PTH concentrations in term, appropriate for gestational age (AGA) infants remained low during the first 2 days of life; a significant (P less than 0.05) and sustained increase in plasma hormone levels was noted starting on day 3. PTH concentrations in IDM and preterm infants remained low for 3 days and a significant hormone increase did not occur until day 4. Hypocalcemia was common in IDM and asphyxiated infants; these infants accounted for two-thirds of all hypocalcemic infants. The profile of plasma calcium in IDM during the first week of life was different than that of any other group of infants. Plasma calcium concentrations remained depressed over this period of time and exhibited a temporary drop on day 4 accompanied by an increase in plasma PTH levels. Asphyxiated infants exhibited low plasma calcium concentrations, despite PTH levels that were significantly (P less than 0.007) higher than those of age-matched term AGA newborns.
